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Jimmunol.1901175.Full.Pdf Type II but Not Type I IFN Signaling Is Indispensable for TLR7-Promoted Development of Autoreactive B Cells and Systemic Autoimmunity This information is current as of September 26, 2021. Sathi Babu Chodisetti, Adam J. Fike, Phillip P. Domeier, Harinder Singh, Nicholas M. Choi, Chelsea Corradetti, Yuka Imamura Kawasawa, Timothy K. Cooper, Roberto Caricchio and Ziaur S. M. Rahman J Immunol published online 3 January 2020 Downloaded from http://www.jimmunol.org/content/early/2020/01/02/jimmun ol.1901175 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2020/01/02/jimmunol.190117 Material 5.DCSupplemental Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 26, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2020 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published January 3, 2020, doi:10.4049/jimmunol.1901175 The Journal of Immunology Type II but Not Type I IFN Signaling Is Indispensable for TLR7-Promoted Development of Autoreactive B Cells and Systemic Autoimmunity Sathi Babu Chodisetti,* Adam J. Fike,* Phillip P. Domeier,*,1 Harinder Singh,† Nicholas M. Choi,* Chelsea Corradetti,‡ Yuka Imamura Kawasawa,x,{ Timothy K. Cooper,‖,2 Roberto Caricchio,‡ and Ziaur S. M. Rahman* TLR7 is associated with development of systemic lupus erythematosus (SLE), but the underlying mechanisms are incompletely under- stood. Although TLRs are known to activate type I IFN (T1IFN) signaling, the role of T1IFN and IFN-g signaling in differential regulation of TLR7-mediated Ab-forming cell (AFC) and germinal center (GC) responses, and SLE development has never been directly investigated. Using TLR7-induced and TLR7 overexpression models of SLE, we report in this study a previously unrecognized Downloaded from indispensable role of TLR7-induced IFN-g signaling in promoting AFC and GC responses, leading to autoreactive B cell and SLE development. T1IFN signaling in contrast, only modestly contributed to autoimmune responses and the disease process in these mice. TLR7 ligand imiquimod treated IFN-g reporter mice show that CD4+ effector T cells including follicular helper T (Tfh) cells are the major producers of TLR7-induced IFN-g. Transcriptomic analysis of splenic tissues from imiquimod-treated autoimmune-prone B6.Sle1b mice sufficient and deficient for IFN-gR indicates that TLR7-induced IFN-g activates multiple signaling pathways to regulate TLR7-promoted SLE. Conditional deletion of Ifngr1 gene in peripheral B cells further demonstrates that TLR7-driven autoimmune http://www.jimmunol.org/ AFC, GC and Tfh responses and SLE development are dependent on IFN-g signaling in B cells. Finally, we show crucial B cell- intrinsic roles of STAT1 and T-bet in TLR7-driven GC, Tfh and plasma cell differentiation. Altogether, we uncover a nonredundant role for IFN-g and its downstream signaling molecules STAT1 and T-bet in B cells in promoting TLR7-driven AFC, GC, and SLE development whereas T1IFN signaling moderately contributes to these processes. The Journal of Immunology, 2020, 204: 000–000. ystemic lupus erythematosus (SLE) is a debilitating au- Ab-forming cell (AFC) and follicular germinal center (GC) toimmune disease mediated by Abs reactive to DNA- and responses are traditionally thought to be involved mainly in anti- S RNA-associated self-antigens. Although extrafollicular pathogen Ab responses, AFCs and GCs can also develop spon- by guest on September 26, 2021 taneously in the absence of purposeful immunization or overt *Department of Microbiology and Immunology, Pennsylvania State University infection (1, 2). Dysregulation in spontaneous AFC (Spt-AFC) and College of Medicine, Hershey, PA 17033; †J. Craig Venter Institute, Rockville, Spt-GC responses in SLE patients and SLE-prone mice promotes MD 20850; ‡Rheumatology Division, Temple University, Philadelphia, PA 19122; xDepartment of Pharmacology, Institute for Personalized Medicine, Pennsylvania State autoreactive B cell survival and pathogenic autoantibody pro- University College of Medicine, Hershey, PA 17033; {Department of Biochemistry and duction (3–8). However, the mechanisms that drive Spt-AFC and Molecular Biology, Institute for Personalized Medicine, Pennsylvania State University spontaneous GC (Spt-GC) responses which can lead to the de- College of Medicine, Hershey, PA 17033; and ‖Department of Comparative Medicine, Pennsylvania State University College of Medicine, Hershey, PA 17033 velopment of autoreactive B cells, autoantibodies and SLE are 1Current address: Immunology Program, Benaroya Research Institute, Seattle, WA. incompletely understood. Genome-wide association studies revealed multiple risk alleles 2Current address: Integrated Research Facility, National Institute of Allergy and Infectious Diseases, Frederick, MD. in the TLR pathway that are strongly associated with SLE de- ORCIDs: 0000-0003-4801-4973 (N.M.C.); 0000-0002-8638-6738 (Y.I.K.); 0000- velopment (9, 10). Overexpression and overactivity of TLR7 are 0002-1379-1118 (R.C.); 0000-0001-8431-9681 (Z.S.M.R.). associated with development of SLE in humans and in mouse Received for publication September 25, 2019. Accepted for publication November models (11–13). Recent collaborative works also have highlighted 18, 2019. the significance of TLR7 in promoting extrafollicular double This work was supported by National Institutes of Health RO1AI091670 to Z.S.M.R., negative B cell populations involved in SLE pathogenesis (8). Lupus Research Alliance Award 548931 to Z.S.M.R., and the Finkelstein Memorial Award to S.B.C. TLR7 gene escape from X chromosome inactivation enhances the B cell response to TLR7 stimulation (14). Studies in the MRL-lpr The sequences presented in this article have been submitted to the Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE141433) under model highlight the opposing inflammatory and regulatory roles accession number GSE141433. for TLR7 and TLR9, respectively, in extrafollicular autoreactive Address correspondence and reprint requests to Dr. Ziaur S.M. Rahman, Pennsylvania B cell responses and SLE development (15). Using a variety of State University College of Medicine, 500 University Drive, Hershey, PA 17033-0850. SLE mouse models, we and others discovered that TLR7 signaling E-mail address: [email protected] specifically in B cells promoted SLE development through for- The online version of this article contains supplemental material. mation of Spt-AFCs and Spt-GCs (11, 16, 17). These data high- Abbreviations used in this article: AFC, Ab-forming cell; ANA, anti-nuclear Ab; GC, germinal center; GN, glomerulonephritis; IMQ, imiquimod; PAS, periodic light the importance of TLR7 signaling in promoting autoimmune acid-Schiff; RNA-seq, RNA sequencing; SA, streptavidin; SLE, systemic lupus AFC and GC responses, leading to the development of autoreac- erythematosus; SmRNP, Smith/ribonucleoprotein; Spt-AFC, spontaneous AFC; tive B cells, autoantibody production and SLE; however, mecha- Spt-GC, spontaneous GC; Tfh, follicular helper T; T1IFN, type I IFN. nisms of TLR7-mediated autoimmunity and SLE development are Copyright Ó 2020 by The American Association of Immunologists, Inc. 0022-1767/20/$37.50 not clearly defined. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1901175 2 REGULATION OF TLR7-DRIVEN AUTOREACTIVE B CELL DEVELOPMENT Type I IFN (T1IFN) and type II (IFN-g) IFN signaling are both studies were conducted at Penn State Hershey Medical Center in ac- implicated in SLE (9, 18). An IFN-a signature is associated with cordance with the guidelines approved by our Institutional Animal human SLE (19, 20). Lupus-prone mice deficient in IFN-aR have Care and Use Committee. Animals were housed in a specific pathogen- free barrier facility. reduced anti-nuclear Abs (ANAs) and renal disease (21). Exoge- nous IFN-a treatment accelerates the SLE phenotype in female Imiquimod treatment 3 (NZW NZB) F1 mice with an early development of anti- For epicutaneous imiquimod (IMQ) treatment, 5% IMQ cream (Glenmark dsDNA Abs and nephritis (22). The administration of IFN-a in Pharmaceuticals) was applied on the ears of mice 3 times weekly for lupus-prone mice also leads to enhanced short-lived AFC and GC 4–12 wk, depending on the experiments as previously described (38, 39). responses (23), and an altered B cell selection in the GCs (24). We For PCR array and RNA-seq sample preparation, mice were treated for 4 wk. To study the systemic autoimmune responses, such as AFC, GC, and others recently showed a B cell–intrinsic role of T1IFN sig- follicular helper T (Tfh), and Ab responses, mice were treated for 8 wk. To naling in loss of tolerance and autoreactive B cell development in evaluate immune complex deposition and kidney pathology, mice were the AFC and GC pathways in lupus-prone mice (25, 26). SLE treated for 12 wk (three times a wk for 8
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