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Expression Il2 Differentiation by Promoting TNFR2 Impairs Th17 Transmembrane TNF−TNFR2 Impairs Th17 Differentiation by Promoting Il2 Expression Patrick G. Miller, Michael B. Bonn and Susan C. McKarns This information is current as J Immunol 2015; 195:2633-2647; Prepublished online 12 of October 3, 2021. August 2015; doi: 10.4049/jimmunol.1500286 http://www.jimmunol.org/content/195/6/2633 Downloaded from References This article cites 76 articles, 37 of which you can access for free at: http://www.jimmunol.org/content/195/6/2633.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 3, 2021 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 © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Transmembrane TNF–TNFR2 Impairs Th17 Differentiation by Promoting Il2 Expression Patrick G. Miller,* Michael B. Bonn,* and Susan C. McKarns*,† The double-edged sword nature by which IL-2 regulates autoimmunity and the unpredictable outcomes of anti-TNF therapy in autoimmunity highlight the importance for understanding how TNF regulates IL-2. Transmembrane TNF (tmTNF) preferentially binds TNFR2, whereas soluble TNF (sTNF) binds TNFR1. We previously showed reduced IL-2 production in TNFR12/2 TNFR22/2 CD4+ T cells. In this study, we generated TNFR12/2, TNFR22/2, or TNFR12/2 TNFR22/2 5C.C7 TCR Il2-GFP mice and report that CD4+ T cell–intrinsic tmTNF/TNFR2 stimulates Il2 promoter activity and Il2 mRNA stability. We further used tmTNF Foxp3 gfp reporter mice and pharmacological TNF blockade in wild-type mice to report a tmTNF/TNFR2 interac- tion for Il2 expression. IL-17 is critical for host defense, but its overabundance promotes autoimmunity. IL-2 represses Th17 differentiation, but the role for TNFR2 in this process is not well understood. We report elevated expression of TNFR2 under Th17-polarization conditions. Genetic loss-of-function experimental models, as well as selective TNF blockade by etanercept and Downloaded from XPro1595 in wild-type mice, demonstrate that impaired tmTNF/TNFR2, but not sTNF/TNFR1, promotes Th17 differentiation in vivo and in vitro. Under Th17-polarizing conditions, elevated IL-17 production by TNFR2-knockout CD4+ T cells was asso- ciated with increased STAT3 activity and decreased STAT5 activity. Increased IL-17 production in TNFR2-knockout T cells was prevented by adding exogenous IL-2. We conclude that CD4+ T cell–intrinsic tmTNF/TNFR2 promotes IL-2 production that inhibits the generation of Th17 cells in a Foxp3-independent manner. Moreover, under Th17-polarizing conditions, selective blockade of CD4+ T cell–intrinsic TNFR2 appears to be sufficient to promote Th17 differentiation. The Journal of Immunology, http://www.jimmunol.org/ 2015, 195: 2633–2647. nterleukin-2 is essential for tolerance against self-Ags, as il- IL-2 that are produced impact the outcome of immune responses. lustrated by the autoimmune phenotype of the IL-2 knockout In naive cells, the Il2 promoter is silent, but an integrated assembly I (KO) mouse (1–3). IL-2 is produced mainly by activated CD4+ of chromatin-remodeling complexes, histone modifications, and T cells. This pleotropic cytokine signals through intermediate transcription factors, including AP-1, NF-kB, NFAT, and OCT-1, 29 affinity (KD ∼ 10 M) CD122 (IL-2Rb)/CD132 (gc) and ligand- facilitate a rapid and transient onset of Il2 promoter activity. Il2 211 specific high-affinity (KD ∼ 10 M) CD122/CD132/CD25 (IL- expression is controlled by the strength and duration of TCR sig- by guest on October 3, 2021 2Ra) receptor complexes that respond to ∼1 nM and ∼10 pM doses naling, costimulation, and rapid Il2 mRNA degradation (8, 10, 11). of IL-2, respectively (4), to activate downstream STAT5, MAPK, The CD28 response element, located 2164 to 2152 bp immedi- and PI3K signaling cascades (5). Consumption of IL-2 in the pe- ately upstream of the transcriptional start site, is especially impor- riphery by CD4+ effector T cells or regulatory T cells (Tregs) con- tant for Il2 gene transcription and posttranscriptional regulation tributes to the control of Th cell differentiation and suppressor Treg of Il2 mRNA stability. function, respectively (6–9). Given the dichotomous role of IL-2 Our knowledge of how different ligand–receptor interactions on immune regulation and the nature by which multiple cell pop- contribute to T cell activation and differentiation has steadily ulations compete for a common pool of IL-2, the rate and amount of grown to include a host of costimulatory molecules. In addition to signal 1 through the TCR and signal 2 (costimulation), we (12) and other investigators (13, 14) have shown that TNFRs promote IL-2 *Laboratory of TGF-b Biology, Epigenetics, and Cytokine Regulation, Center for Cellular and Molecular Immunology, Department of Surgery, University of Missouri production. TNF, similar to other TNF family members (e.g., LIGHT, School of Medicine, Columbia, MO 65212; and †Department of Molecular Micro- FasL, and TRAIL), exists in membrane-bound and soluble forms. biology and Immunology, University of Missouri School of Medicine, Columbia, MO The matrix metalloprotease TNF-converting enzyme cleaves trans- 65212 membrane TNF (tmTNF) from the cell surface to generate a 17-kDa Received for publication February 6, 2015. Accepted for publication July 14, 2015. soluble TNF (sTNF) (15). sTNF and tmTNF preferentially signal This work was supported by National Institutes of Health Grant R01 ES022966 and a University of Missouri Richard Wallace Faculty Incentive Grant Award (both to through TNFR1 (CD120a, p55) and TNFR2 (CD120b, p75), re- S.C.M.). spectively (16, 17). In contrast to the ubiquitous expression of Address correspondence and reprint requests to Dr. Susan C. McKarns, Department TNFR1, TNFR2 is restricted mostly to hematopoietic cells, endo- of Surgery, University of Missouri School of Medicine, M616 Medical Sciences thelium, microglia, and oligodendrocytes. Signaling downstream Building, Columbia, MO 65212. E-mail address: [email protected] of TNFR1 and TNFR2 is distinct, yet overlapping, and is mediated Abbreviations used in this article: 7-AAD, 7-aminoactinomycin D; AHR, aryl hydro- by the recruitment of adaptor proteins and the activation of down- carbon receptor; ARNT, AHR nuclear translocator; cRPMI, complete RPMI; CsA, cyclosporin A; CT, cycle threshold; dKO, double knockout; DN-TNF, dominant- stream transcription factors, including NF-kBandJNK.Incontrast negative TNF; KO, knockout; LAP, latency-associated peptide; LN, lymph node; LT, to TNFR2, TNFR1 contains an intracellular death domain and lymphotoxin; MCC, moth cytochrome c; MFI, mean fluorescence intensity; MLN, mesenteric LN; MOG, myelin oligodendrocyte glycoprotein; pY, tyrosine phosphor- promotes caspase-mediated apoptosis (18, 19). TNFR2 contains ylation; qRT-PCR, quantitative RT-PCR; ROR, retinoic acid–related orphan receptor; intracellular TNFR-associated factor binding domains. We pre- SPLN, spleen; sTNF, soluble TNF; Tg, transgenic; tmTNF, transmembrane TNF; Treg, viously associated TNFR1/TNFR2 double deficiency with im- regulatory T cell; UTR, untranslated region; WT, wild type. paired IL-2 production (20), but the individual contribution of Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 each of these receptors remains undefined. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1500286 2634 TNFR2 REGULATES IL-2 TO CONTROL IL-17 Following activation, CD4+ T cells differentiate into distinct Abs and reagents effector subpopulations characterized by unique cytokines, tran- + TCRVb11 (KT11), CD120a (55R-286), CD120b (TR75-89), CD26 (H194- scription factors, and immune-regulatory properties. CD4 Th17 112), CD278 (C398.4A), and CD62L (MEL-14) were purchased from Bio- T cells are characterized by the expression of retinoic acid–related Legend (San Diego, CA). TCRb (H57-597), CD4 (RM4-5), CD4 (GK1.5), orphan receptor (ROR)-gt and the production of two related CD8a (Ly-2), CD120a (55R-286), CD69 (H1.2F3), CD25 (PC61), TNF effector cytokines, IL-17 and IL-17F. Th17 cells are essential (MP6-XT22), CD45Rb (16A), and CD16/CD32 (2.4 G2) were purchased from BD Biosciences (San Jose, CA). Foxp3 (FJK-16s), CD28 (37.51), and for host protection against bacterial and fungal infections, but latency-associated peptide (LAP; TW7-16B4) were purchased from eBio- too much IL-17 can promote inflammation or autoimmunity (21). science (San Diego, CA). Annexin V and 7-aminoactinomycin D (7-AAD) How TNF regulates Th17 cells is poorly understood. Given the were purchased from BD Biosciences. Lyophilized recombinant mouse 77 233 recent interest in selective activation of TNFR2 as a therapeutic TNF (aa Val –Leu , expressed in Escherichia coli) was purchased from R&D Systems (Minneapolis, MN) as a lyophilized powder, 0.2 mm filtered target, a better understanding of the selective roles of TNFR1 and 2 + in PBS without a carrier protein, stored at 80˚C, and reconstituted in TNFR2 on cytokine production by CD4 T cells is needed. The sterile PBS with 0.01% BSA (Fraction V; Sigma-Aldrich, St. Louis, MO) objective of this study was three-fold: to determine the individual as a carrier protein just prior to use. MCC aa 88–103 and myelin oligo- contribution of TNFR1 and TNFR2 to IL-2 expression, to deter- dendrocyte glycoprotein (MOG) aa 35–55 were purchased from AnaSpec minewhetherregulationofIL-2expressionbyTNFR1orTNFR2 (Fremont, CA). PMA, ionomycin, and cyclosporin A (CsA) were pur- + + chased from Calbiochem-EMD Millipore (Dormstadt, Germany).
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