Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. nldn h ffiin eeomn fTh swl sBcl ieetainadatvto.Thclsalso cells Tfh activation. and CD4 differentiation regulates cell also B IL-21 as pro- help. well cell that as B factors Tfh, for of of important tran- expression development all regulatory the efficient are master suppresses the that the also including IL-4 Bcl-6 upon and CD4 IL-21 depend other [4-6]. CXCL13, of functions (Bcl6) differentiation their via 6 the pathogens and lymphoma mote against process B-cell immunity multi-stage protective factor cell a scription [2]. B is affinity of antibody differentiation GC development increased these Tfh in studies promote of Functional role proliferation to critical and recombination [1-3]. survival a and cells for play switching essential affinity B immunoglobulin they are secondary (GC) antibody Thus, that of center signals follicle with cells. provide germinal cell help switching, B cells B with provide Tfh the class interact to to that immunoglobulin to demonstrated localized is have generally and tonsils, cells be including proliferation helper to tissues, considered their T were lymphoid of regulate cells function Tfh to Historically, fundamental and maturation. The CD4 cells immunity. of B cell subset to B a antigen-specific are of cells opment affinity T including helper Follicular responses, antibody lesions. the active The resolving and and/or complexes. activation limiting Introduction microbial to cell contributing specific B and to lesions localized related periodontal to responsiveness strongly controlling cell contribute for and Tfh critical age to in be by increase cells may An affected maturation Tfh Conclusions: periodontitis, gingival receptors, disease. of of surface and progression health including capacity the showed in genes, complexes in differed T related microbial that later other Unique Tfh genes of the occurred disease. markers Tfh during of transcription with increased number master interactions significantly A the of also factor while were patterns change. transcription factors animals, minimal transcription major young showed and and the or products adult in secreted decreased both increase either (n=40) in apparent disease were genes An with subsets Tfh Results: found cell examined was MiSeq. sites, analysis BCL6, 16S years healthy Microarray aging cells, using matched (12-23 Tfh resolution. to examined at group of clinical were obtained related [adult after samples were differ periodontitis samples microbiome samples may microbiome the in ligature-induced subgingival and and and of and tissues disease, model tissue ligature-induced also these Gingival a periodontitis during in are years)]. in with sites (3-7 occur used they tissues group were should however, Gingival young monkeys cells age); tissues; mulatta inflammation. of Tfh lymphoid Macaca chronic of secondary in footprints Methods: structures in genomic effects. lymphoid critical so tertiary inflammation considered in chronic generally and reflect are circulation cells the in (Tfh) identified cells T helper Follicular Abstract 2020 10, September 4 3 2 1 Gonzalez Octavio Ebersole Jeffrey in Footprints Periodontitis Cell Progressing T Follicular of Transcriptomics Gingival nvriyo uroRico Campus Puerto Sciences of Medical University Rico Puerto of University Kentucky of VegasUniversity Las Nevada of University 1 reah Kirakodu Sreenatha , 2 + eprcl ust[] aoia ertdThmlclsinclude molecules Tfh secreted Canonical subsets[7]. cell helper T 2 + usOrraca Luis , eprclsta r novdi h euainaddevel- and regulation the in involved are that cells helper 1 3 ai Gonzalez-Martinez Janis , + elsubsets, cell T 4 and , Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. h agtdOUslcinfrti td a 8frteautsmlsta oee 8 frasi all in reads of samples. all 88% in covered reads that of samples 91% covered adult that samples the samples oral young for primate ligature the 58 nonhuman in the the was examined throughout in were study and identified OTUs this health OTUs 49 at for Similarly, 396 for obtained of selection samples. compared group [25], were OTU young previously signals targeted the reported microbiome the from the have sufficient from samples we with derived 25 As samples samples and Matching model. matching adults animals. for in the only samples of determined 58 each were in expression tooth gene same gingival (p the analysis coefficient and correlation components V13) bacterial Pearson of a (HOMD a differences Statistical using with Database determined PRJNA516659). assigned determined ID Microbiome were (BioProject were NCBI Oral phylotypes NIH OTUs the Human binned were at deposited Sequences the these were [25]. data previously 24]. and using Raw described [23, have similarity MiSeq classification we sample a as sequence each taxonomic &file&type=R) using (http://www.homd.org/index.php?name=seqDownload from their respective analyzed microbiome on and their the curette based of to a phylotypes composition by total into animals the 36 clustered for the 22] from [21, obtained instrument were samples of bacterial assessment Subgingival factors by local documented of and was depth ligatures site analysis pocket of sampled Microbiome probing removal the and after taken at BOP months samples of disease 2 plaque 1 presence periodontal and subgingival the [?] and of (Initiation/Progression), (BOP) gingival months Determination Probing and 3 on [19] (Resolution). and Bleeding reported 1, mean previously have 0.5, and 3 we mm at excluding as 3.0 examination initiated mouth Periodon- [?] clinical was full (PD) The [20]. disease a Depth scale) [19]. Pocket in 0-5 utilized mean (BOP; Com- scale) was probing by Use (0-5 model on defined and disease bleeding was Care ligature and health Animal a (PPD) tal Institutional depth and pocket Rico the probing Puerto by included of approved examination University was the water protocol of and the (IACUC) vegetables, diet previously mittee primate and reported NIB have fruits Teklad we with 8773, As supplemented (diet was diet primates monkey diet nonhuman commercial The The fiber WI). provided study. 10% was Madison, the and Teklad, in 12-23 fat, included Harlan 5% (age: were animals protein, modified: n=18) Adult years; 20% 3-7 a [16-18]. health fed (age: were periodontal animals for young examined and were n=18) Rico years; Puerto Seca, Sabana at Center ( monkeys Rhesus tissues. gingival the Diet in and also cells Animals aid was Tfh to It functional capacity for effects. the have aging required would to molecules Methods microbiome various related oral the differ may complex dampening and the or tissues of triggering gingival components in genomic the bacterial periodontitis, this in certain reflect of occur that progression periodontitis B would predicted with and macrophages, cells development tissues Tfh gingival cells, with of the in that T As functionally footprints detected hypothesized by and we [13-15]. be infiltrated anatomically microenvironment organs themselves of can often lymphoid organize type secondary cells are can to elements Tfh responses similar cellular that manner immune resident direct These a periodontium, chronic tissue [13]. with the of and plasmacytes including cells, milieu and tissues circulating CXCR5 cells Moreover, Tfh a both The in responses. and that antibody antigens cells proliferation. is zones[10-12]. modulate contain B to cell cell study cytokines B the B this produce GC bind driving both to that into ICOS IL-21 interest cells of and Tfh of particular functions the PD1 cells Of production the of both Tfh and migration regulate CD40LG, differentiated and CD40LG to chemoattraction with of via enhances surface Coupled majority cells receptor cell The B [9]. B (TCR). of receptors the co-stimulation receptor surface on cell cell ligands T and to the cytokines differentiation and both early ICOS, The include CD40LG. IL-6, and by CXCR5 ICOS, driven are PD1, is CXCR5, including Tfh markers, of surface cell crucial display hi PD1 dlibitum ad hi aaamulatta Macaca Bcl6 hi na nlsdcra setting. corral enclosed an in Maf hi SAP t-test n3;1 ae 9fml)hue tteCrbenPiaeResearch Primate Caribbean the at housed female) 19 male, 17 (n=36; ) hi n PSGL1 and (p < .5.Creain fOU ihnteoa irboewere microbiome oral the within OTUs of Correlations 0.05). lo CD200 > rd m sw aedsrbdpeiul [17]. previously described have we as mm, 4 2 oasadcnns[9.Lgtr-nue periodontal Ligature-induced [19]. canines and molars + BTLA < .5.Creain ewe h microbiome the between Correlations 0.05). hi CCR7 lo 8.Bcl epsgasfo Tfh from signals help cell B [8]. Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. h on ape FGdcesdwt ies n XL3adI4wr nrae ndsaesamples. disease in increased were with IL4 comparison and In CXCL13 and process. disease disease the with with decreased increased IFNG each samples CXCL13 young and the IL21 and baseline, from changes decreased limited 3C-D showed CD57 and Fig. resolution, (0.5 and initiation and progression disease with disease process increased resolution with an the disease decrease overtime. demonstrated In in to the even IL6RA tended disease. and and through disease CD10 that throughout through Only months) change decreased increases showed baseline. much and receptors to animals show these the compared points. young of samples samples not data majority in young the elevated did all adults the transformed appeared in and across in contrast, was CD200 and adults, Generally, Only data samples than The samples. receptors. young lower resolution surface months). and was Tfh-associated (5 adult level to resolution all expression profiles and across response months), normalize the 3 to summarizes 1, z-score (0.5, a disease using (BL), health in animals samples 3A-E young Figure and adult T-bet/TXB21, in factor, comparison the samples. transcription expression was resolution the Th1 Gene note the samples samples. of in tissues resolution latter increased Also in gingival (ROR the only even RORC young samples. was in and and resolution and expression particularly progression, groups, in adult age and cells, baseline the initiation both Tfh to in disease both for returning RORA In BCL6 levels in with decreases with cells. significant was progression, helper expression disease T of factor of phases transcription subsets in the increase at presented primary of groups each month both for 3 in the genes changes at gene primarily 2 Tfh groups progression. of both Figure with disease in pattern decreased during overall BCL6 CD200 months in The and 3 increase progression. increased the and disease also was 1 in were note of levels late IRF4 Also expression CD40LG and point gene CXCL13 time animals. IFNG, altered BTLA, adult while in the samples. overlap levels, in receptors, adult considerable disease expression was surface and IRF4 There young including and the decreased. genes, significantly in animals, CXCL13 young related all BTLA, the were Tfh In with CD200 the and observed disease. during of were increased number increases significantly were a striking factors transcription demonstrated and result products secreted The samples. tissue ( young from tissues periodontitis 1 and Figure age with number: profiles 0.05. expression accession gene under [?] Tfh (www.ebi.ac.uk) value base p data a ArrayExpress by Results the considered into was sample uploaded significance two Statistical been groups differences, E-MTAB-1977. age mean differences. has The significant investigate data MO). had to that Louis, The genes St. used For (Partek, ANOVA. were 6.6 way version normalization, one t-tests software quintile using Suite compared probe-level Genomics initially with Partek were algorithm the (RMA) in Average implemented Multi-array as Robust the using estimated ( (n=40) . genes 26-29] Tfh for [17, previously extracted described RNA have total Analysis we Data and methods GeneChip collected to similar surgically the USA) were to CA, sites hybridization Clara, disease via and analysis healthy microarray of samples tissue analysis Gingival mRNA and collection sample tissue Gingival umrzsfl-hne ngn xrsinfrte4 f ee htwr xmndi gingival in examined were that genes Tfh 40 the for expression gene in fold-changes summarizes rvdsasmayo eeepeso hne agtn h atrrgltr transcription regulatory master the targeting changes expression gene of summary a provides rsnsasmlraayi o yoieceoieepeso.I dls L0adIL17F and IL10 adults, In expression. cytokine/chemokine for analysis similar a presents rvd naayi ftearyo eecagscmaigrsossi dlsadyoung and adults in responses comparing changes gene of array the of analysis an provide al 1 Table i.1A Fig. eetree nti td.Teepeso neste costesmlswere samples the across intensities expression The study. this in targeted were ) n dl ( adult and ) i.1B Fig. nmlgnia ise oprdt aeiehealthy baseline to compared tissues gingival animal ) 3 ® hssGn . 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Data may be preliminary. hwdmnmlcag ihdsaei on nml u a infiatyicesdltri ies nthe in disease na¨ıve in CD4 from later cells increased cytokine development Tfh significantly role this cell of was critical for Tfh generation but mRNA a for induces animals the plays fashion IL-12 young factor, IL-21 autocrine in animals. transcription STAT3 an and disease adult the in with cells through change acts IL-6 Tfh minimal by also of showed induced It development is formation. for IL-21 GC While required resolution. and [40-42]. IRF4 with all 39]. production and levels are Ig 38, STAT3 baseline development[34, regulating TGFß Both to cell in and decreased Tfh B-cells. IL-23, and impacts GC IL-12, progression, progression that inducing IL-21, and both IL-21 disease initiation for of are disease the role BATF production at cells at for and increased Tfh particularly factors was IRF4 STAT3 with for transcription groups, change crucial groups. critical age minimal also also cells age showed both are is B both BATF STAT3 in to from 36]. significantly points. cells tissues 35, increased sampling Tfh in differentiation[10, levels IRF4 disease of low Tfh however, with Generally positioning early disease; noted the for [13]. EBI2 also factors directing and were transcription is age PSGL1, regulatory essential genes levels CCR7, cell both 3 Bcl6 of helper from these downregulation high T tissues and of other for CXCR5 gingival from role of differed in upregulation major pattern increased through (BCL6, the A factors was and transcription progression factors. BCL6 various disease transcription including in 33-37]. genes for later Tfh required IRF4)[4, particularly of are groups, c-MAF, array they BATF, an as of ASCL2, expression bacteria, STAT3, gene these commensal targeted of as study well may biology This cells as the Tfh pathogens, of lesions, cells to quality. periodontitis clarification B response responses of mechanistic to antibody effective tissues help Bcl6, a gingival for provide the of to important can within expression essential that be specifically elevated populations is More cell with tissues conditions. T structures cells inflamed inflammatory of lymphoid (Tfh) chronically range ectopic tertiary the helper these form Understanding termed follicular within can ICOS[1]. been T tissues and have prototypical inflamed PD1, and demonstrate CXCR5, chronically centers that into is germinal [14] migrate study localized functional (TLS) system that this facilitate with for immune lymphocytes would note structures that gingival adaptive These particular lymphoid aggregates Of reflected major lymphoid interactions. 32]. that accumulate identified cell 27, commonly progression, have [26, T-B tissues genes disease health, we inflamed Ig with in chronically Additionally, rearranged tissues that of later gingival expression in particularly and substantial [19]. subsets with model, rodent resolution cell triggering the T to clinical we various in related periodontitis, and of responses ligature-induced particularly footprints lesions, of genomic Cell mammals, disease model the [31]. most primate on challenge progressing functions nonhuman effects antigenic in effector a aging including cell identified Using shown stimuli T have been different models. and have to disease B primate both respond features nonhuman of types the similar maturation cell of with and various Th2, each development These for subsets GATA3 support of 30]. and Th1, development pathogens 6, for The from 4, T-bet/TXB21 Bcl6[1, factors: Tfh. is transcription and cells lineage-specific Treg, by Th9, driven ROR Th17, is subsets Th2, cell Th1, Th including Tfh differences, these functional that was CD4 interest The of samples. of Also young cytokines/chemokines composite and correlations. adult the the Discussion microbiome both of and for in Additionally, represented enrichment CD84, were an IL6RA, relationships correlations. showed gene-bacterial CD10/MME, these profiles samples. IL17A resolution expression for CD40LG, and and genes enriched receptors disease, IL12 the health, particularly cell highlight into cell were We stratified that factors, samples CD3D/E/G showed animal cells. transcription young findings Tfh of and by adults These interactions in produced includes altered products were This soluble that and correlation CD57/B3GAT1. complexes. negative receptors, only bacterial broad to surface very correlation with negative a correlated strong exhibited significantly a relationship 4 showed complex a 5 6 that demonstrated complex Figure was while complexes interest genes, these Of Tfh of 20/40 genes. Three to of pattern set complexes. overlapping identified an 5 to showed samples resolution α/γ + o h7 OO o h,adFX3frTe el.Teciia rncito atrfrTfh for factor transcription critical The cells. Treg for FOXP3 and Th9, for FOXO1 Th17, for rvdsashmtco rti neato ewr eae oteThgnseaie that examined genes Tfh the to related network interaction protein a of schematic a provides eprcl ouaini uasi opsdo utpesbeswt la hntpcand phenotypic clear with subsets multiple of composed is humans in population cell helper T 5 + el 4,4] hl L2 a been has IL-23 while 44], [43, cells T Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. ihTBcl neatos D0 sagyorti ufc oeueta samme fteimmunoglobulin the of member a associated is functions that down-regulate molecule surface specifically glycoprotein cells a is Tfh CD200 only with interactions. not environment. associated cell is related inflammatory T-B biomolecules it potentially with this However, of again in number [64]. process, cells cells a disease Tfh T Finally, the of mature in communication circulating early and on increased the localization absent substantially of over virtually the was T localization control is but to immature in enhancing and cells, process of cells role Tfh to marker disease B on a contribute a GC expressed the with could and is in consistent that cells CD10/MME/neprilysin points is B lesion Additionally, and This time periodontal disease. early developing during samples. interactions at the resolution host-bacterial within primarily in increased help animals levels significantly cell young was baseline receptor Tfh and to this adults returned for Tfh- expression then both naive gene and of regulating The in tissues factor [63]. gingival crucial lesions. nodes a in lymph periodontal is is draining the signaling that from S1PR1, of sphingolipids egress receptor, plasma-membrane stage cells Its consistent of this adult trafficking. metabolite process, at both immune-cell active disease responses for from biologically essential immune the samples a adaptive in In is and later (S1P) cells 62]. up-regulated Sphingosine-1-phosphate Tfh were [61, of genes functions TCR role cells CD150 Tfh increased Tfh and and optimal on an integrin CD84 receptors and related with via SLAM both contact switching The primarily animals, cell SAP. class young appear requires T-B antibody cells and DCs prolonged B and with in with help interaction interactions engaged Tfh B-cell Tfh are of in the phase role sustained While Through the critical receptors, [58-60]. a 2008). development have (Calpe Tfh to cells adaptor to receptors (SAP/SH2D1A) Tfh protein these GC (SLAM)-associated enables molecule on activation molecule identified lymphocyte PD1 signaling been elevated of for have activity that mRNA the model. molecules found the disease CD150/SLAM been signaling in this and changes TCR has in CD84/SLAM5 via no It observed However, APCs was proliferation[57]. engages signaling. receptor and Tfh TCR Tfh cells not dampening important B but through Tfh this on proliferation to cells, PD1L related Tfh B to expression limits binds to gene actually cells help in Tfh transient differences on varied provides PD1 the that of age. one periodontitis upon representing cell based within thus efficient functions disease, reported adult Tfh been in for only receptor also cells IL6RA IL-6 have dendritic the in functions of responses follicular primarily cell deletion and from T cell-specific disease numbers arise T with Furthermore, cell to change [53-55]. dendritic response felt lesions a albeit generally was 52], is expression, CD40LG receptor production responses[5, antigen-presenting for cell and IL-6 message B proliferative animals. in control improved helps increases adult with [50, that population that molecule cells B-cell co-stimulatory noted B memory We major the capacity. of a on as phenotype cells CD25 a B of represents on and expression receptor induces CD40 generally interaction the were to This mRNA binds 51]. c-Maf cells of mRNA Tfh levels on ICOS expressed although IL-21[37]. CD40LG animals, of young IL-4 and production and adult through IL-21 both cells for in expression these unaffected. disease important c-Maf of in also induces maintenance later broadly is engagement increased and ICOS is ICOS is STAT3[12]. formation Importantly, (B7h) and Tfh [39]. IL-6 molecules supports ICOS-L IL-21, SLAM that ligand, CXCR5 of interaction on control The antigen-specific dependent its under 49]. baseline be in and production cells[48, to to increases B cells shown dropped on for been then T expressed critical has constitutively and activated is is process on in and ICOS/ICOS-L disease tissues expressed later of the non-lymphoid increased was is in APCs, CCR7 that on earlier ICOS of expressed tissues expression appeared 15, samples. in young 9, but change resolution [1, and no elevated, CXCL13 while in adult also samples, ligand was both resolution its the CXCR4 in with in interaction seen. CXCR5 elevated via remained CXCR5) in actually regions CCR7, (CXCR4, increases and down-regulating cell disease chemokine and significant B CXCR5 to identified and up-regulating Tfh We Bcl6 IL21R) of by 31]. (IL6R, migration cells model. enhancing B cytokine disease CXCR5 with various inflammatory co-localize with of chronic cells this Tfh expression 10]. in elevated receptors[7, level show mRNA [45-47]. the cells diseases at inflammatory Tfh various altered in were formation factors autoantibody these of of induction Neither the to contribute nvivo in nldn eeti f ucin 5] h eidnii oe hwdicessin increases showed model periodontitis The [56]. functions Tfh in defect a including , 6 + PD1 α hi I6A eut nimpaired in results (IL6RA) chain + f el n CBclsand cells GC-B and cells Tfh Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. a eehne yimnzto,spot htlclzdThfntosi igvltsusmypoiean disease. provide of may magnitude tissues and gingival progression in the functions that controlling production Tfh for antibody mechanism localized systemic regulatory that and immune data supports strong local adaptive existing immunization, detailing these important with by 87] favor molecules Coupled 86, enhanced which [20, co-stimulatory be etc.), responses. primates CXCR5, can immunoglobulin cell nonhuman SLAM, and B-cell T-B [79-85] mature (eg. and humans and receptors in survival T-APC successful other B-cell to of and promote leading PD1,) engagement also interactions CD40LG, that the ICOS, cytokines through TCR, of and production (eg. the footprint. production, through Tfh of antibody positive mediated the demonstrated are and relationship within complex functions genes the bacterial cell of same Tfh to groups the Thus, different approach specific note, with between Of systems correlations patterns genes. broad a correlation Tfh of negative the genes, visualization and of a Tfh panels provided and specific levels complexes specific (eg. expression bacterial of with genes gene significance with Tfh bacteria to statistical correlated of abundance of estimate panel significantly bacterial could the complexes were we with of complexes while correlated in Finally, negatively correlations these Tfh-D1Y). or differences bacteria of Tfh-R4A, positively only unique certain Tfh-R2A, either were Tfh-H1A, of Secondly, showing mixtures generally composed were as that microorganisms. generally simply genes well but of not multiple expression. bacteria, as were types commensal gene complexes these oral sites, Tfh versus these of the resolution periodontopathogens Moreover, with as high and correlated First, microbiomes. considered a disease strongly historically young detected. afforded that and were health, bacteria bacteria analysis adult in of of this the differed of complexes complexes nonhuman outcomes of or complexes Multiple this number bacteria The finite profiles. using certain a expression pattern that Thus, the were gene potential with the there microbiome over the [74-78]. the “control” minimal discern of of development with interrelationship to level lesion samples the expression examined “point-in-time” the gene we are disease, of of progressing these some dynamics of however, of model levels true health; primate altered the with versus genes disease regarding specific of of knowledge expression indicative the host as in in changes changes microbes of specific relationships to identified This related have complexes bacteria bacterial periodontitis. [69-73]. and/or of of bacteria changes sites the summation tissue the of the responses disease triggers ecology, profile is and at disease detailed responses, periodontitis more the these microbiome a in in dysregulates However, commensals dysbiotic changes, paradigm and response a pathogens host current and drives both to sites The which of microbiome disease biology at altered symbiotic process. microbiome reflects healthy disease dysbiosis the of a the recognized quantity reflecting from be and must changes quality transition it the functions, clinical Tfh in resulting to alterations related from the genes result of downstream footprint changes cell group. the the these there in Tfh age that differentiation is changes either substantive STAT5 Tfh of these in represses noted inhibitor disease we tissues. also As with potent gingival would STAT5 mRNA STAT5 the another although in in Thus, is change IL-2RA. young low no signaling and of generally was adults engagement IL-2 were both IL-2 that in levels of environment disease reported gene target regulatory with significantly cell IL-2 been increased T generally, levels has the up-regulated mRNA samples, of significantly It IL2RA portion was While important gene an [68]. tissues. differentiation this be gingival cell to BTLA, Tfh predicted the with regulating be As in might negatively that immune in 9]. disease checkpoint in during responses[5, important involved only immune an molecule for the overall as adaptive regulatory encodes to with emerged SELPLG and during gingival contribute has interacts adhesion function tissues. PSGL-1 primate gingival may an BTLA However, the nonhuman is which in trafficking. that the help cell disease, [67]. (PSGL-1) Tfh In during ligand-1 cells through glycoprotein occurring increased Th2 functions. P-selectin responses significantly on immune effector were the except cell of levels activation regulation T mRNA cell inhibits BTLA T immunoglobulin and tissues the during molecule to induced belonging co-stimulatory T- also is B7H4 and receptor thus B- co-inhibitory It Similarly, points, a time is lesion. disease CD272) superfamily. inflammatory all production chronic across eg. mediator developing molecule (BTLA, inflammatory the this attenuator nsitu in ean ob lcdtd tde fhmngnia rncitmsadascae targeted associated and transcriptomes gingival human of Studies elucidated. be to remains 7 Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. .Terl fIO nteCC5 olclrBhle elmitnnei vivo Okumura in H, maintenance Yagita cell K, Tezuka T J, helper Ma B T, follicular Yamazaki CXCR5+ N, the Harada blood in Y, Human ICOS Usui :2340-8. of H. Y, role Ueno Kojima The K, J, K. Takeda Dullaers Banchereau H, E, Akiba differentially V, Foucat that 12. G, Pascual subsets specific Zurawski M, contain and L, Punaro T cells secretion Bourdery follicular versus antibody EM, T R, of support Lavecchio 1 counterparts Ranganathan are N, Helper cells SE, T T Sabzghabaei Bentebibel CXCR5(+)CD4(+) Regulating S, N, Mechanisms Oh Schmitt Molecular M, R, H. Morita Ueno 11. SE, Humans Bentebibel in Differentiation Y, Cell Liu Helper N, Follicular Schmitt Cells 10. T Helper Follicular IC. MacLennan D, 2016; Yu MA, ogy Linterman CG, Vinuesa Molecular the 9. Into Pathology Insights R. and Nurieva Immunity N, EV, repressor Galkina Simpson Helper-Mediated transcriptional H, Follicular :1884. L, Zhou The S, Zheng T Bieerkehazhi CG. M, A, of Vinuesa Sahoo Linterman Mechanisms TC, CR, M, Waseem Mackay Srivastava L, commitment Qin CR, EL, lineage Parish 8. Sutcliffe cell Bcl6 QJ, Y, helper C. Li He follicular Dong CS, T SK, directs YH, Ma Lee Bcl-6 Wang LM, IA, Parish TD, Tsai Matskevitch S, JI, development Rao Ellyard S, cell Tanaka D, Yu cells XO, helper Yang helper follicular 7. follicular GJ, T T Martinez and of Y, development Bcl6 the Chung Kaech of mediates RI, JM, regulation Nurieva Odegard vivo X, Dong In 6. JS, J. Weinstein A, Craft Chandele S, 2010; D, orchestrates Crotty Immunol Eto BCL6 AL, SG, S. Hernandez Dent Crotty K, SM, Hansen A, AC, Melnick Poholek EK, 5. Haddad M, mechanisms Bothwell distinct MA, multiple :539-53. via Kroenke differentiation JP, cell Nance Tfh K, (TFH) Hatzi cells T 4. CD4 disease helper in Follicular roles Diseases and S. function, and Crotty differentiation, Discovery 3. cell of helper follicular Decade T S. A Crotty Biology: 2. Cell Helper Follicular T :1132-48. S. JGM Crotty and measures, 1. clinical the experiment. the of the to preparation of contributed for conduct LO References responsible and was analysis. husbandry SSK animal for the DNA manuscript. collection, to bacterial sample the contributed and and of data mRNA clinical preparation experiment, tissue and the gingival data, of conduct the design, of the for interpretation responsible of initial were OAG content for and the JLE Stromberg with interest A. of conflict Microarray Contributions Dr. no the Author and acknowledge thank authors assistance, also We The technical Kentucky. report. invaluable data. of this microarray their University the Oral for the for of at Kentucky Center normalization to Dentistry the University gratitude and of of our P40RR03640, College express grant Core the We by in P20GM103538. supported Research grant (CPRC) Center Health Health Research of Primate Institute Caribbean National by the supported was work This Acknowledgement 34 :335-68. 185 :313-26. . muiy2011; Immunity 34 . :108-21. . elrprs2016; reports Cell nulrve fimnlg 2011; immunology of review Annual . 8 cec 2009; Science . . muiy2009; Immunity h ora feprmna eiie2015; medicine experimental of Journal The 325 16 . :1082-95. :1001-5. rnir nimnlg 2018; immunology in Frontiers 31 :457-68. . . muiy2014; Immunity nulrve fimmunol- of review Annual . . muo 2005; Immunol J 29 muiy2019; Immunity :621-63. 41 :529-42. 175 212 . 50 9 J Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. 9 eaA ataacauV ahskmrS oe C em K altS,BatcayaI Boyce I, Bhattacharyya SM, Wallet J, RK, Verma Gonzalez-Martinez MC, Lopez L, S, Orraca Sathishkumar V, tissues S, Bakthavatchalu mucosal A, Shen Meka oral in AJ, 29. expression Stromberg gene S, apoptosis Kirakodu on aging M, 59. of Novak Effects John JL. OA, Ebersole Gonzalez periodontitis Ebersole and 28. J, ageing Gonzalez-Martinez in pathways A, presentation Stromberg antigen KC, 2014; L, tissue Chen Periodontol gingival L, Orraca of Orraca KC, analysis S, Comparative Kirakodu Chen JL. MJ, CB, Novak OA, Huang Gonzalez R, 27. Polarization Tissues Nagarajan Macrophage Gingival A, Reflecting Periodontitis Profiles Stromberg and Expression Aging S, Gene Ligature- in Differential Kirakodu of JL. Profiles MJ, Ebersole Microbiome Novak J, Martinez-Gonzalez J. OA, Span Ebersole Gonzalez of Life OA, the speed Gonzalez 26. across and J, Primates sensitivity Martinez Nonhuman improves Gonzalez in J, UCHIME Periodontitis Chen R. Induced S, Knight Kirakodu C, Quince 25. JC, Clemente BJ, detection Haas chimera RC, mothur: Introducing Edgar CF. BB, Weber 24. Oakley microbial DJ, RA, comparing Horn Lesniewski Van and EB, GG, describing Hollister Thallinger for communities M, B, software sequencing Hartmann Stres community-supported JR, JW, Illumina platform-independent, Sahl Hall open-source, MiSeq CJ, T, Robinson the Ryabin DH, SL, on Parks Westcott data PD, Schloss sequence 23. amplicon sequencing analyzing dual-index a for of Development pipeline Ligature- PD. platform Schloss of curation SK, Profiles Highlander and NT, Microbiome Baxter strategy J. SL, Westcott Ebersole JJ, Lifespan OA, Kozich systemic the Gonzalez 22. Across on J, Primates disease Martinez Nonhuman oral Gonzalez in and J, Periodontitis age Chen Induced of S, Kirakodu Effects MJ. primates 21. Novak nonhuman in J, parameters Gonzalez-Martinez immune MJ, and Steffen inflammatory JL, A, Burgos Ebersole J, periodontitis 20. Gonzalez-Martinez of L, resolution and Orraca 2014. progression S, Periodontol initiation, Shen during Clin AJ, profiles J Stromberg expression gene MJ, Novak Cytokine OA. S, Gonzalez Kirakodu inflammatory JL, systemic Ebersole on diet 19. Matti- primates reduced-calorie JC, a nonhuman Gunsolley of in KF, effects Novak parameters gender DR, immune Differential Dawson MJ. Apoptotic and GL, Novak Branch-Mays JL. DK, MA, Ingram Ebersole Reynolds JA, MJ, son MJ, Steffen Novak JL, J, tissue Ebersole gingival Gonzalez-Martinez 18. aged PM, in Huggins expressed differentially AJ, are Stromberg genes OA, Gonzalez Ebersole J, 17. Gonzalez-Martinez tissues L, mucosal 2013; Orraca oral in death in S, cells cell expression Shen gene regulatory programmed AJ, apoptosis follicular on Stromberg on T aging S, and of Kirakodu Effects cells and MJ, JL. helper Novak Immunity follicular OA, T Gonzalez in D. 16. Cells Yu L, T Graca VR, Helper Fonseca diseases Follicular Y, rheumatic Wei J, Editorial: Deng G. 15. Fousteri S, Salek-Ardakani MP, Tissues Autoimmunity Inflamed Cicalese Chronically in 14. Cells B Help That Cells :1924. T DA. Rao 13. . plEvrnMcoil2013; Microbiol Environ Appl . plEvrnMcoil2009; Microbiol Environ Appl . rnir nimnlg 2020; immunology in Frontiers . 41 . iifrais2011; Bioinformatics auervesRemtlg 2019; Rheumatology reviews Nature :327-39. 18 :249-59. 27 79 :2194-200. . 75 :5112-20. muooia netgtos2015; investigations Immunological :7537-41. . 11 eidna e 2008; Res Periodontal J :1042. 9 . etRs2011; Res Dent J 15 :475-90. . lnVcieImnl2008; Immunol Vaccine Clin . . netImn2019. Immun Infect netImn2019; Immun Infect . ppoi nitrainljournal international an : Apoptosis . 43 rnir nimnlg 2018; immunology in Frontiers 90 :500-7. :880-6. 44 . ppoi 2013; Apoptosis :643-64. 87 15 . :1067-75. 18 . Clin J :249- 9 . Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. omteto av ua D()Tclst h olclrhle TF) ellnaei nue by induced is Early lineage SG. cell Tangye (T(FH)) EK, Deenick helper B, follicular Santner-Nanan T the R, to Nanan cells A, T Chan CD4(+) DT, alters human Avery deficiency naive S, beta1 of Suryani receptor commitment CS, IL-12 humans Ma H. in Ueno response Blanken- 44. JL, cell MV, Casanova Tran helper F, J, follicular Hamlin Banchereau T S, DA, vivo Boisson-Dupuis Savino in SE, V, Bentebibel Pascual L, D, Bourdery J, ship Bustamante N, Schmitt potential therapeutic 43. with sword disease double-edged human a of Interleukin-21: 2014; WJ. understanding Discov Leonard our R, the enhancing Spolski in - 42. IL-21 biology Cytokine IL-21 Associated the in 2015; and Advances Immunol Subsets SG. Cell Tangye Helper Follicular 41. T Asthma P. of helper Zhou Therapy T T, and of Tian Zheng Pathogenesis independent AM, F, but Jetten interleukin-21 Gong SS, by Watowich mediated YH, 40. lineages Wang is cell L, cells 17 Ma helper or HS, H. follicular 2, Kang T Ueno XO, 1, of Yang J, Generation D, C. Banchereau Hwang Dong Y, K, Q, TFH Chung Venuprasad human RI, L, of Nurieva differentiation Bourdery 39. the I, promote Munagala to STAT3-STAT4 cells via SE, helper signaling Bentebibel cells T co-opts Y, follicular TGF-beta Liu of cytokine development The N, the costimulatory Schmitt The in VK. IL-21 38. Kuchroo and AH, c-Maf Sharpe of IC, cells Ho expression TH-17 M, and the Mitsdoerffer regulates Transcription AM, M. ICOS Paterson Lohoff H, molecule TW, Jin AT, Mak Bauquet R, differentiation Bothur Jacob 37. cell 2012; G, C, A T-helper Giel Dong follicular S C, R, Brendel through U Nurieva B, formation Sci RA, Camara center Acad Kroczek H, germinal Raifer A, determines E, Elli IRF4 Abass C, factor W, Paul Ackermann M, K, Batf Kellner Huber responses EJ. A, E, Taparowsky antibody Brustle CH, normal N, for Bollig Kim required MR, 36. function Logan cell J, 2010; T Liao medicine and SG, experimental B Kang of of C, Wang aspects multiple KL, coordinates cells Jordan-Williams AY, STAT3 BC, helper Functional JM, Kreins follicular Betz SG. Smart Tangye PD, T S, EK, 35. human Arkwright Deenick Choo factor of JL, S, MA, Casanova French Transcription generation DA, Boisson-Dupuis LG, S, Fulcher the C. Nonoyama MC, J, Flier compromises Y, Cook Bustamante Dong der deficiency P, Minegishi Gray M, van SS, L, M, P, Kilic Batten Wong Wei K, J, Chen A, Peake Magdorf H, X, Chan D, Yan Qi DT, Engelhard D, RI, Avery Q, Averbuch Nurieva CS, Tian F, Ma Chu H, development 34. X, T-helper-cell Clevers Wang follicular W, A, initiates Wang Chen 2 homologue B, SS, achaete-scute Periodontitis: Zhong Neelapu in X, H, Functions Chen Nakatsukasa Immune X, Aging Cell Liu in B Microbiome 33. Oral of Stromberg MV, the Analysis Thomas to Transcriptome LL, Responses Cunningham OA. JG, Tissue Martinez Gonzalez Mucosal L, SN, Orraca MJ, Pandruvada Novak cells SS, A, helper Kirakodu follicular JL, Ebersole T Crotty of ME, 32. function Pipkin and AW, development 2010; circuits the Goldrath immunology repressor-of-repressor Understanding molecular B, via Y. & Yu cells Chung S, RI, helper Nurieva Belanger follicular 31. M, T Rossi of factor J, Truong transcription 2020; nexus infection- CE, Immunol Faliti the gingivalis is H, Porphyromonas Bcl-6 Diao L. S. J, Kesavalu Choi JL, Ebersole 30. profiles HV, transcriptional Baker bone and RJ, tissue Lamont induced M, Handfield BF, . a muo 2014; Immunol Nat 13 34 21 . :379-95. a muo 2009; Immunol Nat :107-15. :777-89. 109 . muiy2008; Immunity 15 :8664-9. :856-65. 7 207 :190-7. :933-42. . 10 rnir nimnlg 2019; immunology in Frontiers 29 :167-75. :138-49. . o rlMcoil2010; Microbiol Oral Mol . lo 2013; Blood 10 . rnir nimnlg 2016; immunology in Frontiers 121 :3375-85. 10 . aue2014; Nature . :2918. lo 2012; Blood 25 :61-74. 507 119 :513-8. :3997-4008. . 7 . a e Drug Rev Nat :272. . h Journal The . urOpin Curr rcNatl Proc . Cellular . Nat Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. 0 ann L iH uK,DtaM oe-orge ,CegJ aeadE,GranRN, Germain EK, process Wakeland adhesion J, cell Cheng cell:B J, T multistage Gomez-Rodriguez a M, CD84 require Dutta and responses protein, KT, SLAM-associated center Lu integrins, germinal antigen involving H, Optimal upon Qi responses PL. JL, antibody Schwartzberg Cannons promote CCR7(lo)PD- and precursor activity 60. Circulating cell PL, D. Yu Schwartzberg Tfh A, Z, indicate L, Veillette Li Zhu cells DS, CR, Y, reexposure Riminton Mackay T Ding MC, S, CG, CD4(+) Rockman Cook Vinuesa CXCR5(+) K, JR, SG, Vandenberg 1(hi) Tangye X, Ghali Sun R, GT, N, Brink Belz Chevalier F, CS, A, Mackay Ma Karnowski X, strategy C, Hu Wang a YA, W, Leong as Wei LM, interactions Tsai cell J, T:B He dependent 59. SAP of Modulation S. vaccination Crotty improve C, to Havenar-Daughton Differentiation J, Cell L, Hu Tfh Pasman 58. of and HK, Regulators primary Lee S. in X, Devadas signaling Yan S, IL-6 Mohanty S, 2016; of Yu GM, role N, cell-intrinsic Jogdand T Hoshi 57. R. Y, Medzhitov Gao J, SD, Bruning H, Pope responses Zhao memory FT, dendritic B, Wunderlich Yordy and D, I, chemokines Schenten Brodsky between SA, Relationship Nish RA. Mesquita 56. FO, periodontitis Costa chronic potential Jr., human and CM, in autophagy Queiroz cells via GR, clearance Souto microbial 55. cells: Dendritic disease CW. periodontal Cutler for RM, consequences immunobiological Arce periodontitis Bcl6 AR, of El-Awady IL-6-mediated pathogenesis the for 54. of required aspects is STAT1 Molecular I. edge: Chapple Cutting :7-17. J, S. Meyle Crotty differentiation C, 53. cell Lao helper JA, centers follicular Yang germinal early D, and for Eto cells induction YS, dendritic Follicular Choi J. 52. Banchereau O, 1997; Bouteiller Res de 1996; Immunol G, Cytol universe? Grouard Rev immune YJ, the Liu of center 51. the At ligand. CD40 The receptor RA. :59-70. ICOS Flavell S. IS, Crotty Grewal C, repressor 50. transcriptional Lao the L, of Monticelli induction via RJ, differentiation Johnston cell effector TC, Bcl6 versus a Escobar cell D, helper in follicular Eto pathway T R, instructs ICOS/ICOS-L Kageyama YS, the disease Choi ameliorates Targeting and 49. JA. responses cell Harker helper CM, follicular T Lloyd disrupts 2019; SA, asthma Allergy Walker allergic established CJ, cells of mononuclear Pyle model mouse blood FI, peripheral Uwadiae in activity 48. SIRT1 Toussirot and arthritis L, IL-23 Sukumar Coquard rheumatoid C, serum with Vidon WM, Dysregulated patients KA, G. Khan Interleukin-23-Induced Blumenschein of X, Herbein Guillot DJ. K, C, A, Cua Kumar Prati Hirahara M, Godfrin-Valnet E, JJ, G, Cells W, Abbas O’Shea 17 Vahedi D, Wendling MJ, Helper B, 47. T McGeachy Joyce-Shaikh of TK, Pathogenicity Y, McClanahan Promotes Blimp-1 Kanno S, Factor Sadekova Transcription Y, CJ, Chen disease: Haines R, bowel S, inflammatory Cytokine Jain and CM. Figueredo periodontitis 46. RG, with Fischer patients AT, of Carvalho study tissues F, exploratory intestinal Brito An and MA, gingival Siqueira in R, expression Lira-Junior JS, Menegat 45. IL-12 . . 7 muo elBo 2009; Biol Cell Immunol muiy2011; Immunity :520. . muiy2013; Immunity 74 166 :650-62. . Lf 2014; eLife :139-79. . 34 . rhOa il2016; Biol Oral Arch urOi io 2013; Virol Opin Curr :932-46. 39 87 3 :770-81. :e01949. :590-600. . . eidno 2014; Periodontol J LSOe2015; One PLoS 66 3 :141-6. :363-70. 11 . . 10 muo 2013; Immunol J eidno 002015; 2000 Periodontol . 85 :e0119981. muiy2010; Immunity :1416-23. 190 32 . muiy2016; Immunity :253-65. :3049-53. . 69 . eidno 002015; 2000 Periodontol rnir nimmunology in Frontiers :160-80. 44 :131-42. . Int 69 16 . Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. h niioyrcpo TAi -olclrhle el n nBcl ml ypoyi lymphoma/chronic lymphocytic of small expression B-cell High L. in Xerri and D, cells Olive R, helper Nicollas leukemia T-follicular R, lymphocytic in Bouadallah BTLA F, Rey receptor provide B, inhibitory Chetaille that the ML, cells Thibult H, effector M’Hidi non-Th1/Th2 cells 67. as helper follicular role T cells their CR. Mackay B reflecting MS, for Rolph profile, help MR, transcriptional Hodge distinctive N, Frank a R, express Newton SG, Tangye target T, Chtanova therapeutic circulating potential of 66. a phenotype as The 2012; CD200 RJ. immunology defines Cornall developmental arthritis RA, rheumatoid & Luqmani with Clinical P, involved patients Bowness cells in O, cells T Morteau T helper Martin SC, follicular-helper follicular Bennett C, Monvoisin A, producing cells Chakera J, IL-4 B Priol human 65. lymphoma Le of R, follicular subset Jean of a MS, survival delineates Braza the CD10 J, in K. Misiak Tarte C, P, Artchounin Gaulard centers S, N, Sphingosine-1-phosphate germinal Hoeller P, T. in Ame-Thomas Okada retention JG, 64. cell Cyster T M, helper Kubo follicular S, 2014; for Hori medicine critical JA, is germinal Green underlie 2 N, interactions receptor Takahashi cell T-B S, dynamic Moriyama back: 63. and cells a B helpless function formation, to center and cells development germinal T center during SAP-less From cells H. B Qi with 62. interactions cell T Z. Shulman model N, three-step Davidzohn A, Biram 61. 4 al D eshl ,Dme T aaao N dnicto fMse euao ee in Genes Regulator Master of Identification PN. Papapanou RT, Demmer MK, M, Annavajhala Kebschull CW, cohort:The Periodontitis Watson AD, Human elderly S, an Sawle Burkett in status B, 74. health periodontal Paster oral clinical A, of and Kokaras study microbiome ancillary B, Subgingival WHICAP Cheng JM. E. H, Noble Zaura AC, WG, Park Wade professionals Uhlemann PN, MS, healthcare Tonetti Papapanou oral AM, Pedersen for periodontal V, 73. update Meuric of an PD, pathogenesis - Marsh the microbiome M, Hannig oral in IL, The communities Chapple microbial M, Kilian of 72. Role MA. Curtis caries A, and interactions Simon-Soro diseases host A, and communities Mira dynamic 71. microbiota: oral The 2018; G. Microbiol disease Hajishengallis Rev periodontal H, Nat in Koo microbiota RJ, the Lamont of 70. role The cells TE. Dyke B Van to PI, help 2020; Diaz cell MA, T Curtis of 69. history brief A S. Crotty 68. 8 eshl ,PppnuP.Teueo eeary ndcpeigteptoilg fperiodontal of pathobiology the deciphering in arrays gene of use The PN. MicroRNAs Papapanou PN. diseases Papapanou M, M, Kebschull Kebschull tissues RT, 78. gingival Demmer in R, genes Celenti target P, their Guarnieri and C, Stoecklin-Wasmer differences Molecular PN. 77. Papapanou P, periodontitis Pavlidis aggressive AL, transcrip- Boulesteix and RT, tissue chronic Demmer Gingival between P, PN. Guarnieri M, Papapanou Kebschull P, Pavlidis 76. P, phenotypes Guarnieri periodontitis B, distinct Grun identify RT, tomes Demmer M, Kebschull 75. 83 . :14-25. ehd o il2010; Biol Mol Methods . 211 . muo 2004; Immunol J muooia eiw 2019; reviews Immunological . :1297-305. lnProotl2017; Periodontol Clin J . . etRs2016; Res Dent J mJCi ahl2009; Pathol Clin J Am 16 :745-59. . 666 173 muooia eiw 2012; reviews Immunological :385-93. :68-78. . 95 . eidno 2020. Periodontol J etRs2012; Res Dent J :1010-7. 2012 . . 4Spl18 Suppl 44 etRs2013; Res Dent J lo 2015; Blood 288 132 . etRs2014; Res Dent J :948218. :37-48. :589-96. 12 . auervesImnlg 2015; Immunology reviews Nature 125 :S23-S38. 91 :2381-5. :934-40. 247 92 . rts etljunl2016; journal dental British 93 :1081-8. :24-35. :459-68. . h ora fexperimental of Journal The . 15 eidno 2000 Periodontol :185-9. 221 :657-66. . . Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. XR -- oi hmkn eetr4RR A eae rhnRcpo ;mse rncito atrTh17 factor interleukins transcription 1 to master Receptor responses Th17 C; Sphingosine-1-Phosphate cellular factor Receptor mediates transcription Orphan 3; master Related Transcription A; RAR Of Receptor Activator Orphan And Related Transducer RAR Signal (SLAM) molecule activation 1 lymphocytic Beta signaling Factor cells the Growth B Transforming of Ligand on receptors P PD1L regulating Selectin to Adapter binds S1PR1 1A; T-cells; Containing activated Domain SELPLG/PSGL1 antigen SH2 RORC on receptor Inhibitory STAT3 RORA SH2D1A/SAP TGFB1 receptor cytokine PD1/PDCD1 IL-21 activity immunoregulatory with Cytokine receptor 21; 17A cytokine Interleukin Interleukin 12 IL-7 Interleukin 10 Interleukin 17F Interleukin IL21R 4 Factor Regulatory Interferon repressor or activator transcriptional IL17A a as IL7R IL21 cytokines acts of IL12 Oncogene; family IL-12 of IL17F part IL10 23; Interleukin c-maf/MAF IRF4 receptor cytokine Th2 IL-2 factor transcription gamma master 4 Interferon 3; Interleukin Th9 Protein factor Binding transcription GATA master Treg O1; factor Box transcription IL23 Forkhead master P3; Box Forkhead 5 Receptor IL2RA Chemokine Motif 4 C-X-C Receptor GATA3 Chemokine IFNG 183 Motif Receptor C-X-C 13 Protein-Coupled FOXO1 Ligand IL4 G Chemokine proliferation Motif T-cell C-X-C Costimulates FOXP3 OX-2; EBI2/GPR183 receptor CXCR5 cytokine IL-6 cells CXCR4 B cells on T CD40 family of binds (SLAM) CXCL13 subset ligand; molecule family responses; activation surface (SLAM) immune lymphocyte cell molecule in glycoproteins Signaling CD200 activation T role on lymphocyte Essential epitope Signaling APCs carbohydrate on CD150/SLAMF1 L2/HNK-1 MHCII of binds Biosynthesis APCs component; metallopeptidase on CD84/SLAMF5 membrane TCR MHCII IL6RA Neprilysin; binds APCs component; on TCR CD57/B3GAT1 MHCII lymphocytes binds on component; receptor 7 CD40LG TCR Inhibitory Receptor attenuator; Chemokine (CD272) Motif Associated C-C CD10/MME Lymphocyte Tfh T factor And transcription CD4 B master Repressor; Transcription Factor BCL6 CD3G Transcription ATF-Like Zipper Leucine CD3E Basic 2 Factor Transcription BHLH CD3D Family Achaete-Scute CCR7 BTLA Fxn BCL6 BATF ASCL2 ID Gene 1: periodontitis Table to mediators susceptibility inflammatory to fluid related crevicular Gingival primates T. nonhuman 2000; Filloon in Immunol RE, of gingivitis Singer of Responses SC, bacteriology Holt Systemic D, and Associated Cappelli and JL, Microbes Ebersole Oral 87. of Acquisition JE. Primates Delaney Nonhuman SC, Newborn Holt JL, Ebersole 86. indices putative clinical to response with antibody correlation systemic periodontitis: 1993; and chronic Local Immunol M. with McDonald patients TW, in MacFarlane J, periodontopathogens Mooney in DF, actinomycetemcomitans Kinane Actinobacillus gingival 85. to in antibody gingivalis fluid Porphyromonas crevicular Gingival disease to D. periodontal G Cappelli JL, immunoglobulin status Ebersole specific disease 84. site of to Levels Acti- related to DF. are antibody Kinane fluid fluid crevicular J, crevicular Mooney gingival of response 83. specificity immune Antigenic humoral MJ. and Steffen microflora D, actinomycetemcomitans subgingival Cappelli nobacillus JL, implications in Ebersole systemic Changes 82. DF. and Kinane local J, therapy fluid: Mooney periodontal following crevice IB, gingival Darby anti- in 81. produced responses Locally immune JG. Humoral 2003; Tew 2000 JL. Periodontol AM, ag- Ebersole Best from fluid CN, 80. crevicular Brooks gingival in JA, patients antibodies Burmeister periodontitis lipoprotein gressive CR, low-density anti-oxidized Berry and HA, phosphorylcholine Schenkein 79. olclrhle elgn xrsintargets expression gene cell helper follicular T 15 8 :65-8. :19-26. . rlMcoilImnl1994; Immunol Microbiol Oral 31 :135-66. . . . lncladvcieimnlg 2014; immunology vaccine and Clinical lnProotl2001; Periodontol Clin J eidno 2004; Periodontol J . etRs2000; Res Dent J . rlMcoilImnl1997; Immunol Microbiol Oral 75 9 13 :335-44. 79 :146-53. 28 :1362-70. :796-805. 21 :21-8. 12 :112-6. . . rlMicrobiol Oral rlMicrobiol Oral . eeI Fxn ID Gene Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. CSIdcbeTCl otmltr id CS nBclsTbtTB1TBxTasrpinFco 1 atrtasrpinfco Th1 factor transcription master 21; Factor Transcription T-Box T-bet/TXB21 cells correlation. B negative on significant ICOSL a binds denotes Costimulator; red Cell and T correlation Inducible positive significant denotes Blue functions. 2: Table Fxn ICOS ID Gene infiatcreain fmcoim T opee ihgnsrltdt f hntp and phenotype Tfh to related genes with complexes OTU microbiome of correlations Significant 14 eeI Fxn ID Gene Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. Health ComplexCD3GIL6RACD40LCD3DIL12CategoryID CD57CD10IL17ACXCR5BTLA IL21RCD84CD150CD4 H1A Tfh- 539 alocis tor fac- i- Fil- 531 tans comi- mycetem- no- acti- A. 619 valis gi- gin- romonas phy- Por- fied si- clas- un- [XIII] caceae coc- to- tostrep- Pep- 246 sp. ponema Tre- 363 sum io- tid- fas- terium Fretibac- 439 sp. 1] [G- roflexi Chlo- 361 sp. Fretibacterium + + + - - - 15 a L1INP1I2 CSSTAT3CD3ECXCR4BATFASCL2IRF4 ICOS IL23 IFNGPD1 TGFB1CD200SELPLGIL7R IL21 maf CCR7S1PR1 EIB2 c- + + + Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. aeoy DComplexCD3GIL6RACD40LCD3DIL12CategoryID CD57CD10IL17ACXCR5BTLA IL21RCD84CD150CD4 H2A Tfh- 014 oralis ria se- Neis- fied si- clas- un- ter bac- i- gat- gre- Ag- 600 enoeca votella Pre- fied si- clas- un- votella Pre- fied si- clas- un- lonella Veil- fied si- clas- un- totrichia Lep- fied si- clas- un- Selenomonas - - + + + 16 a L1INP1I2 CSSTAT3CD3ECXCR4BATFASCL2IRF4 ICOS IL23 IFNGPD1 TGFB1CD200SELPLGIL7R IL21 maf CCR7S1PR1 EIB2 c- Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. aeoy DComplexCD3GIL6RACD40LCD3DIL12CategoryID CD57CD10IL17ACXCR5BTLA IL21RCD84CD150CD4 H3A Tfh- 664 tophilum mal- ponema Tre- 820 sp. votella Pre- 643 dia me- ter- in- votella Pre- 155 sp. 1] [G- laceae lonel- Veil- 151 gena sputi- lenomonas Se- 357 colens pis- ter dobac- mi- Pyra- fied si- clas- un- ponema Tre- fied si- clas- un- Bacteria - - 17 + + + + a L1INP1I2 CSSTAT3CD3ECXCR4BATFASCL2IRF4 ICOS IL23 IFNGPD1 TGFB1CD200SELPLGIL7R IL21 maf CCR7S1PR1 EIB2 c- Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. aeoy DComplexCD3GIL6RACD40LCD3DIL12CategoryID CD57CD10IL17ACXCR5BTLA IL21RCD84CD150CD4 H4A Tfh- 035 sp. Haemophilus 833 catarrhalis Moraxella 279 sp. romonas phy- Por- 046 rum lo- bil- mor- Gemella 526 sp. votella Pre- cus coc- to- Strep- 105 mum fir- in- Eubacterium + + + 18 a L1INP1I2 CSSTAT3CD3ECXCR4BATFASCL2IRF4 ICOS IL23 IFNGPD1 TGFB1CD200SELPLGIL7R IL21 maf CCR7S1PR1 EIB2 c- Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. Disease ComplexCD3GIL6RACD40LCD3DIL12CategoryID CD57CD10IL17ACXCR5BTLA IL21RCD84CD150CD4 D1A Tfh- unclassified lenomonas Se- 317 sp. votella Pre- 155 sp. 1] [G- laceae lonel- Veil- 203 sp. terium sobac- Fu- 664 tophilum mal- ponema Tre- fied si- clas- un- terium Fretibac- 151 gena sputi- lenomonas Se- fied si- clas- un- lonella Veil- fied si- clas- un- Leptotrichia + + + + + - - 19 a L1INP1I2 CSSTAT3CD3ECXCR4BATFASCL2IRF4 ICOS IL23 IFNGPD1 TGFB1CD200SELPLGIL7R IL21 maf CCR7S1PR1 EIB2 c- Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. aeoy DComplexCD3GIL6RACD40LCD3DIL12CategoryID CD57CD10IL17ACXCR5BTLA IL21RCD84CD150CD4 D2A Tfh- 600 enoeca votella Pre- 584 cola ti- den- ponema Tre- 361 sp. terium Fretibac- fied si- clas- un- ponema Tre- fied si- clas- un- [XIII] caceae coc- to- tostrep- Pep- 363 sum io- tid- fas- Fretibacterium - - + + + + + 20 a L1INP1I2 CSSTAT3CD3ECXCR4BATFASCL2IRF4 ICOS IL23 IFNGPD1 TGFB1CD200SELPLGIL7R IL21 maf CCR7S1PR1 EIB2 c- Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. aeoy DComplexCD3GIL6RACD40LCD3DIL12CategoryID CD57CD10IL17ACXCR5BTLA IL21RCD84CD150CD4 D4A Tfh- D3A Tfh- unclassified terium sobac- Fu- 246 sp. ponema Tre- 619 valis gi- gin- romonas phy- Por- 273 talis dodon- en- Porphyromonas Porphyromonadaceae 046 rum lo- bil- mor- Gemella 833 catarrhalis Moraxella 279 sp. romonas phy- Por- 058 sp. cus coc- to- Strep- 035 sp. Haemophilus + + + 21 a L1INP1I2 CSSTAT3CD3ECXCR4BATFASCL2IRF4 ICOS IL23 + IFNGPD1 TGFB1CD200SELPLGIL7R IL21 maf CCR7S1PR1 EIB2 c- Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. Resolution ComplexCD3GIL6RACD40LCD3DIL12CategoryID CD57CD10IL17ACXCR5BTLA IL21RCD84CD150CD4 R1A Tfh- 160 par dis- lonella Veil- fied si- clas- un- lonella Veil- fied si- clas- un- votella Pre- 291 cola ti- den- votella Pre- 122 formis ci- cronu- mi- phaera Megas- 311 sp. votella Pre- 035 sp. Haemophilus 161 parvula lonella Veil- fied si- clas- un- Streptococcus - 22 + + a L1INP1I2 CSSTAT3CD3ECXCR4BATFASCL2IRF4 ICOS IL23 IFNGPD1 TGFB1CD200SELPLGIL7R IL21 maf CCR7S1PR1 EIB2 c- Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. aeoy DComplexCD3GIL6RACD40LCD3DIL12CategoryID CD57CD10IL17ACXCR5BTLA IL21RCD84CD150CD4 R2A Tfh- unclassified lenomonas Se- 769 skii socran- ponema Tre- fied si- clas- un- lenomonas Se- fied si- clas- un- totrichia Lep- 165 morbi Catonella 317 sp. votella Pre- 058 sp. Streptococcus - - + + + + + + + + + 23 a L1INP1I2 CSSTAT3CD3ECXCR4BATFASCL2IRF4 ICOS IL23 IFNGPD1 TGFB1CD200SELPLGIL7R IL21 maf CCR7S1PR1 EIB2 c- Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. aeoy DComplexCD3GIL6RACD40LCD3DIL12CategoryID CD57CD10IL17ACXCR5BTLA IL21RCD84CD150CD4 R3A Tfh- unclassified terium sobac- Fu- 279 sp. romonas phy- Por- fied si- clas- un- tophaga cy- no- Cap- 046 rum lo- bil- mor- Gemella fied si- clas- un- Fretibacterium - 24 a L1INP1I2 CSSTAT3CD3ECXCR4BATFASCL2IRF4 ICOS IL23 IFNGPD1 TGFB1CD200SELPLGIL7R IL21 maf CCR7S1PR1 EIB2 c- + Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. aeoy DComplexCD3GIL6RACD40LCD3DIL12CategoryID CD57CD10IL17ACXCR5BTLA IL21RCD84CD150CD4 R4A Tfh- 584 cola ti- den- ponema Tre- fied si- clas- un- ponema Tre- 531 tans comi- mycetem- no- acti- A. 105 mum fir- in- terium bac- Eu- 526 sp. votella Pre- 439 sp. 1] [G- roflexi Chlo- 203 sp. Fusobacterium - + + + + + + + + + + 25 a L1INP1I2 CSSTAT3CD3ECXCR4BATFASCL2IRF4 ICOS IL23 IFNGPD1 TGFB1CD200SELPLGIL7R IL21 maf CCR7S1PR1 EIB2 c- Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. aeoy DComplexCD3GIL6RACD40LCD3DIL12CategoryID CD57CD10IL17ACXCR5BTLA IL21RCD84CD150CD4 R5A Tfh- 041 sp. bus ul- fob- Desul- 363 sum io- tid- fas- terium Fretibac- 273 talis dodon- en- romonas phy- Por- 619 valis gi- gin- romonas phy- Por- 361 sp. terium Fretibac- fied si- clas- un- [XIII] caceae coc- to- tostrep- Pep- 539 alocis Filifactor - - 26 + a L1INP1I2 CSSTAT3CD3ECXCR4BATFASCL2IRF4 ICOS IL23 IFNGPD1 TGFB1CD200SELPLGIL7R IL21 maf CCR7S1PR1 EIB2 c- Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. Health ComplexCD3GIL6RACD40LCD3DIL12CategoryID CD57CD10IL17ACXCR5BTLA IL21RCD84CD150CD4 H1Y Tfh- 363 sum io- tid- fas- terium Fretibac- 531 tans comi- mycetem- no- acti- A. 361 sp. terium Fretibac- fied si- clas- un- terium Fretibac- fied si- clas- un- terium sobac- Fu- 046 rum lo- bil- mor- Gemella - - 27 + a L1INP1I2 CSSTAT3CD3ECXCR4BATFASCL2IRF4 ICOS IL23 IFNGPD1 TGFB1CD200SELPLGIL7R IL21 maf CCR7S1PR1 EIB2 c- Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. aeoy DComplexCD3GIL6RACD40LCD3DIL12CategoryID CD57CD10IL17ACXCR5BTLA IL21RCD84CD150CD4 H2Y Tfh- 313 sp. votella Pre- 664 tophilum mal- ponema Tre- fied si- clas- un- ponema Tre- 246 sp. ponema Tre- 600 enoeca votella Pre- 584 cola ti- den- ponema Tre- 643 dia me- ter- in- Prevotella - + 28 a L1INP1I2 CSSTAT3CD3ECXCR4BATFASCL2IRF4 ICOS IL23 IFNGPD1 TGFB1CD200SELPLGIL7R IL21 maf CCR7S1PR1 EIB2 c- Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. Disease ComplexCD3GIL6RACD40LCD3DIL12CategoryID CD57CD10IL17ACXCR5BTLA IL21RCD84CD150CD4 D1Y Tfh- H3Y Tfh- 246 sp. ponema Tre- fied si- clas- un- [XIII] caceae coc- to- tostrep- Pep- fied si- clas- un- terium Fretibac- fied si- clas- un- Bacteroidetes 820 sp. votella Pre- 439 1]sp. [G- roflexi Chlo- 526 sp. votella Pre- 161 parvula lonella Veil- fied si- clas- un- Bacteria + + + + + + + ------29 a L1INP1I2 CSSTAT3CD3ECXCR4BATFASCL2IRF4 ICOS IL23 IFNGPD1 TGFB1CD200SELPLGIL7R IL21 maf CCR7S1PR1 EIB2 c- + Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. aeoy DComplexCD3GIL6RACD40LCD3DIL12CategoryID CD57CD10IL17ACXCR5BTLA IL21RCD84CD150CD4 D2Y Tfh- ponema Tre- 782 fusca votella Pre- fied si- clas- un- terium Fretibac- fied si- clas- un- 619 valis gi- gin- romonas phy- Por- 304 sp. votella Pre- 584 cola ti- den- ponema Tre- 165 morbi Catonella fied si- clas- un- Bacteroidetes - - - + 30 a L1INP1I2 CSSTAT3CD3ECXCR4BATFASCL2IRF4 ICOS IL23 IFNGPD1 TGFB1CD200SELPLGIL7R IL21 maf CCR7S1PR1 EIB2 c- + Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. aeoy DComplexCD3GIL6RACD40LCD3DIL12CategoryID CD57CD10IL17ACXCR5BTLA IL21RCD84CD150CD4 D3Y Tfh- 526 sp. votella Pre- 279 sp. romonas phy- Por- fied si- clas- un- tophaga cy- no- Cap- 317 sp. votella Pre- 345 1]sp. [G- SR1 035 sp. Haemophilus - - + 31 a L1INP1I2 CSSTAT3CD3ECXCR4BATFASCL2IRF4 ICOS IL23 IFNGPD1 TGFB1CD200SELPLGIL7R IL21 maf CCR7S1PR1 EIB2 c- + + Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. aeoy DComplexCD3GIL6RACD40LCD3DIL12CategoryID CD57CD10IL17ACXCR5BTLA IL21RCD84CD150CD4 D4Y Tfh- unclassified 1] [G- laceae lonel- Veil- 155 1]sp. [G- laceae lonel- Veil- fied si- clas- un- ponema Tre- 782 fusca votella Pre- fied si- clas- un- terium Fretibac- fied si- clas- un- ria te- Bac- 439 1]sp. [G- roflexi Chlo- 363 sum io- tid- fas- terium Fretibac- 619 valis gi- gin- romonas phy- Por- 304 sp. votella Pre- 584 cola ti- den- ponema Tre- fied si- clas- un- Bacteroidetes ------32 a L1INP1I2 CSSTAT3CD3ECXCR4BATFASCL2IRF4 ICOS IL23 IFNGPD1 TGFB1CD200SELPLGIL7R IL21 maf CCR7S1PR1 EIB2 c- + Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. aeoy DComplexCD3GIL6RACD40LCD3DIL12CategoryID CD57CD10IL17ACXCR5BTLA IL21RCD84CD150CD4 R5Y Tfh- 539 alocis tor fac- i- Fil- 361 sp. terium Fretibac- 058 sp. cus coc- to- Strep- fied si- clas- un- laceae teurel- Pas- 046 rum lo- bil- mor- Gemella - 33 a L1INP1I2 CSSTAT3CD3ECXCR4BATFASCL2IRF4 ICOS IL23 IFNGPD1 TGFB1CD200SELPLGIL7R IL21 maf CCR7S1PR1 EIB2 c- + Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. Resolution ComplexCD3GIL6RACD40LCD3DIL12CategoryID CD57CD10IL17ACXCR5BTLA IL21RCD84CD150CD4 R1Y Tfh- 1] [G- 317 sp. votella Pre- 833 catarrhalis Moraxella fied si- clas- un- terium bac- Eu- fied si- clas- un- roflexi Chlo- 363 sum io- tid- fas- terium Fretibac- 539 alocis tor fac- i- Fil- fied si- clas- un- votella Pre- 526 sp. votella Pre- 820 sp. votella Pre- 619 valis gi- gin- romonas phy- Por- 105 1]infirmum [XI][G- laceae lonel- Veil- 223 sp. totrichia Lep- 361 sp. terium Fretibac- 439 1]sp. [G- terium Fretibac- 304 sp. Prevotella ------34 a L1INP1I2 CSSTAT3CD3ECXCR4BATFASCL2IRF4 ICOS IL23 IFNGPD1 TGFB1CD200SELPLGIL7R IL21 maf CCR7S1PR1 EIB2 c- + + Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. eeepeso ees osgicn orltos n Asgie h T a o ersne nthe in represented not was OTU the and signifies OTU NA the between and correlation correlations, significant significant a denotes no + – sites. levels, resolution expression and gene disease, health, in and groups 3: Table ComplexCD3GIL6RACD40LCD3DIL12CategoryID CD57CD10IL17ACXCR5BTLA IL21RCD84CD150CD4 R3Y Tfh- R2Y Tfh- infiatcreain fidvda atra Tswt f ee nsmlsfo ohage both from samples in genes Tfh with OTUs bacterial individual of correlations Significant unclassified ria te- Bac- 161 parvula lonella Veil- 313 sp. votella Pre- 246 sp. ponema Tre- fied si- clas- un- 600 enoeca votella Pre- fied si- clas- un- terium sobac- Fu- 317 sp. votella Pre- 833 catarrhalis Moraxella fied si- clas- un- Bacteroidetes Prevotella - - - - 35 + + a L1INP1I2 CSSTAT3CD3ECXCR4BATFASCL2IRF4 ICOS IL23 IFNGPD1 TGFB1CD200SELPLGIL7R IL21 maf CCR7S1PR1 EIB2 c- Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. rvtlas.33––––+–1 2 1 1 – 1 + 2 NA + – – 2 2 – NA + – – – 3 3 3 NA – – – – 3 – – 3 – 3 + + – + 3 – – + – – – + + 3 – – + – – – – 3 – – – – + 3 – 3 – 3 – + + – 3 + + – – – 4 + 3 + + – – + – – + – + 4 Bacteroidetes – 4 + – – – Pasteurellaceae – + – – 4 – + + unclassified – Aggregatibacter 411 – II parasanguinis Streptococcus 4 + + 313 sp. – Prevotella + – 357 + piscolens + – – + Pyramidobacter + – – + 782 – 5 fusca – – 4 Prevotella + + + Veillonellaceae – – sp. + Fusobacterium – – + – + + Veillonellaceae + + 5 – 5 + – 5 + Capnocytophaga – 5 – 165 + – + morbi + Catonella – 151 sputigena + Selenomonas – 161 – 6 parvula + + Veillonella – + + – – + Streptococcus + + + – + 6 – Selenomonas + + + + 833 catarrhalis Moraxella – + – + Peptostreptococcaceae – 539 + alocis – Filifactor – + + + 317 + + + sp. + + Prevotella + + 223 + + sp. Leptotrichia + 643 + intermedia – Prevotella + 304 + + sp. + Prevotella + + 820 + + sp. – Prevotella – + + + 105 + infirmum + Eubacterium 273 endodontalis – Porphyromonas + 664 + + maltophilum Treponema 058 TOTAL sp. Streptococcus + + + Resolution 531 – + actinomycetemcomitans + – + A. + unclassified Prevotella Health unclassified Veillonella + + Disease Bacteria – + 246 + + Resolution sp. – Treponema 046 + morbillorum Gemella Health 600 enoeca Prevotella + 279 + Disease sp. Porphyromonas + + 584 + denticola Treponema + Leptotrichia + unclassified Fusobacterium Chloroflexi 619 gingivalis + Porphyromonas 526 sp. Prevotella unclassified Fretibacterium unclassified Treponema 035 sp. Haemophilus 363 fastidiosum Fretibacterium 361 sp. Fretibacterium Bacteria evaluated. were that members microbiome nlsie 3 + + – – + – unclassified G1 p 3 5 + + + + + – 439 sp. [G-1] nlsie 4 + – – + + + unclassified nlsie 2 – – – + + – unclassified nlsie 1 + – – – – – unclassified nlsie 2 – – – + + – unclassified G1 2 2 + + – – + – – – – – – + 155 sp. [G-1] [G-1] nlsie 1 + – – – – – unclassified nlsie 2 + – – + – – unclassified oral [XIII] taxon nlsie 3 + – – – + + unclassified 0 2 – – – + – + 203 DL DL DL ON ON YOUNG YOUNG YOUNG ADULT ADULT ADULT 36 Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969798.89702780 — This a preprint and has not been peer reviewed. Data may be preliminary. opyooaaee––––––0 1 1 1 – – 0 NA NA – – NA NA NA – NA NA – NA NA – – – + – – + – – – – + – – – Peptostreptococcaceae Porphyromonadaceae 122 micronuciformis Megasphaera 041 sp. Desulfobulbus 014 oralis Neisseria 311 sp. Prevotella f eemn 87_20.pptx v8 gingival-transcriptomics-of-follicular-t-cell-footprints-in-progressing-periodontitis manu gene Tfh that denotes the (H), 0 correlations Both file negative healthy symbols tissues. Hosted and in gingival The positive complexes animal significant 0 young both bacterial products. and demonstrated gene. with adult complex secreted particular gene the from are within the samples bacteria nodes (R) of individual resolution orange correlations 0 and and negative (D), or 0 factors, diseased NA positive transcription significant are identify nodes NA green receptors, 6: Figure NA NA interactions. complex NA bacterial assigned ( healthy NA adult sion 5: Figure NA NA interactions. complex NA bacterial assigned z- ( comparing NA healthy timepoints. means young and group animals sion normalized all denote across 4: Points gene Figure specific months). a NA (5 of resolution expression clinical NA for and scores months) 3 – 1, (0.5, baseline. ( from factors fold-change – transcription as expressed 3: p point at time Figure baseline each at from animals different significantly adult – and denotes and young Asterisk – – asterisk for means The ROR group Th2, denote means. - GATA3 – months) group Th1, (5 - denote resolution bet/TXB21 bars and p The 2: months) at baseline 3 Figure animal. from 1, – each difference (0.5, significant for disease signifies – – samples bracket with healthy horizontal expression baseline in to fold-change – compared as expressed are data 1: – Figure – Legends Figure TOTAL 291 denticola Prevotella 443 sp. Prevotella 769 socranskii Treponema 160 dispar Veillonella SR1 G1 p 4 1 + – – – – – 345 sp. [G-1] eta fcreain ewe atra Tsrltv bnac n niiulgn expres- gene individual and abundance relative OTUs bacterial between correlations of Heatmap expres- gene individual and abundance relative OTUs bacterial between correlations of Heatmap ceai fptnilpoenitrcoeaogThascae ee.Bu oe r surface are nodes Blue genes. associated Tfh among interactome protein potential of Schematic xrsinlvl fThgnsi igvltsusfo on ( young from tissues gingival in genes Tfh of levels Expression xrsino atrtasrpinfco ee o aiu ust fCD4 of subsets various for genes factor transcription master of Expression -cr ausfrThsraercpos( receptors surface Tfh for values Z-score A A E ,dsae ( diseased ), [XI] ,dsae ( diseased ), nautadyugaia igvlsmlsotie nhat B) uigdisease during (BL), health in obtained samples gingival animal young and adult in ) nlsie AN A0 NA NA NA – – – unclassified vial at available B B ,adrslto ( resolution and ), ,adrslto ( resolution and ), / - α/γ DL DL DL ON ON YOUNG YOUNG YOUNG ADULT ADULT ADULT 52 21 72 148 28 17 17 32 29 25 h7 OO h,FX3–Te,BL f el] Points cells]. Tfh - BCL6 Treg, – FOXP3 Th9, - FOXO1 Th17, https://authorea.com/users/355423/articles/478655- 37 B & A C < C 0.01. ape.Bxspoieetmt fgn and gene of estimate provide Boxes samples. ) ape.Bxspoieetmt fgn and gene of estimate provide Boxes samples. ) ,ctknsceoie ( cytokines/chemokines ), < 0.01. A n dl ( adult and ) + B epcls[T- cells help T D & C nml.The animals. ) ,and ),