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NFAT Transcription Factors Promote the Generation of Follicular Helper T Cells in Response to Acute Viral Infection

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NFAT Transcription Factors Promote the Generation of Follicular Helper T Cells in Response to Acute Viral Infection Cutting Edge: NFAT Transcription Factors Promote the Generation of Follicular Helper T Cells in Response to Acute Viral Infection This information is current as Gustavo J. Martinez, Joyce K. Hu, Renata M. Pereira, Jordan of September 25, 2021. S. Crampton, Susan Togher, Nicholas Bild, Shane Crotty and Anjana Rao J Immunol 2016; 196:2015-2019; Prepublished online 5 February 2016; doi: 10.4049/jimmunol.1501841 Downloaded from http://www.jimmunol.org/content/196/5/2015 Supplementary http://www.jimmunol.org/content/suppl/2016/02/04/jimmunol.150184 Material 1.DCSupplemental http://www.jimmunol.org/ References This article cites 32 articles, 12 of which you can access for free at: http://www.jimmunol.org/content/196/5/2015.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 25, 2021 • No Triage! Every submission reviewed by practicing scientists • 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 © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Cutting Edge Immunology Cutting Edge: NFAT Transcription Factors Promote the Generation of Follicular Helper T Cells in Response to Acute Viral Infection † ,1 † Gustavo J. Martinez,* Joyce K. Hu, Renata M.x Pereira,* Jordan{ S.‖ Crampton, Susan Togher,* Nicholas Bild,‡ Shane Crotty,†, and Anjana Rao*, , ,# Follicular CD4+ Th (Tfh) cells provide B cell help in motif) receptor 5 (CXCR5) and the lineage-defining tran- germinal center reactions that support class switching, scription factor B-cell CLL/lymphoma 6 (Bcl6) (8–10). Bcl6 somatic hypermutation, and the generation of high- does not act alone, and other transcription factors have also affinity Abs. In this article, we show that deficiency been identified as key regulators of Tfh differentiation, in- + in NFAT1 and NFAT2 in CD4 T cells leads to im- cluding STATs, Maf, BATF, IRF4, ASCL2 (reviewed in Refs. Downloaded from paired germinal center reactions upon viral infection 11, 12), and LEF-1 and TCF-1 (13, 14). NFAT2 is highly because of reduced Tfh cell differentiation and defec- expressed in Tfh cells (15); however, the roles played by tive expression of proteins involved in T/B interactions NFAT family members in Tfh cells are not well understood. and B cell help, including ICOS, PD-1, and SLAM Tfh cells have enhanced calcium signaling with NFAT nu- family receptors. Genome-wide chromatin immuno- clear translocation compared with Th1 cells, suggesting that precipitation data suggest that NFAT proteins likely NFATs may have preferential responsibilities in Tfh cells http://www.jimmunol.org/ compared with Th1 cells (16). In this article, we investigated directly participate in regulation of genes important the role of NFAT1 and NFAT2 in the generation of Tfh cells for Tfh cell differentiation and function. NFAT pro- and GC responses to acute viral infection. teins are important TCR and Ca2+-dependent regula- tors of T cell biology, and in this article we demonstrate Materials and Methods a major positive role of NFAT family members in Mice and infections Tfh differentiation. The Journal of Immunology, SMARTA [lymphocytic choriomeningitis virus (LCMV) gp66-77-IAb–spe- 2 2 2016, 196: 2015–2019. cific] CD45.1+ mice (17) were crossed with Nfat1 / , Nfat2fl/fl CD4Cre,or 2 2 Nfat1 / Nfat2fl/fl CD4Cre mice (2). All mice were maintained in specific by guest on September 25, 2021 pathogen-free barrier facilities and used according to protocols approved by uclear factor of activated T cells (NFAT) transcription the La Jolla Institute for Allergy and Immunology animal care and use 3 5 factors are key regulators of T cell activation (1) and committees. Mice were infected i.p. with 2 10 PFU LCMV Armstrong 5 strain. The adoptive transfer experiments using SMARTA cells were per- N exhaustion (2). NFAT1, NFAT2, and NFAT4 are formed as previously described (17), unless otherwise stated. Postinfection, expressed in cells of the immune system and have important splenocytes were harvested and cells were stained with Abs against cell-surface roles in T cell development and function (3). Although NFAT markers as previously described (17). LCMV-specific serum IgG was quan- tified by ELISA as previously described (18). ELISA data were analyzed by family members make similar contacts with DNA (4), they area under the curve (AUC). AUC analysis better accounts for both the show distinct expression patterns and functions, as judged by quantity and the quality of the IgG, because it accounts for the shape of the the nonoverlapping phenotypes of mice deficient in individual curve. AUC total peak area above baseline calculations (GraphPad Prism 6.0) NFAT family members (5, 6, and reviewed in Ref. 7). was done for each individual sample, log transformed. + Follicular CD4 Th (Tfh) cells are essential for mediating Isolation and culture of T cells B cell help and inducing germinal center (GC) responses re- Spleens and lymph nodes were harvested from 6- to 8-wk-old mice. Naive quired for most high-affinity Ab responses. Tfh cells have CD4+ cells were purified using EasySep kit (Stem Cell) and activated with been characterized by their expression of chemokine (C-X-C anti-CD3 and anti-CD28 as previously described (2). *Department of Signaling and Gene Expression, La Jolla Institute for Allergy and postdoctoral fellowship from the Jane Coffin Childs Memorial Fund (to G.J.M.); and a Immunology, La Jolla, CA 92037; †Department of Vaccine Discovery, La Jolla Institute postdoctoral fellowship from the Pew Latin American Fellows Program in the Biomed- for Allergy and Immunology, La Jolla, CA, 92037; ‡Genomics Core, The Scripps ical Sciences (to R.M.P.). x Research Institute, Jupiter, FL, 33458; Division of Infectious Diseases, Department { Address correspondence and reprint requests to Dr. Gustavo J. Martinez at the current of Medicine, University of California, San Diego, La Jolla, CA 92037; Department ‖ address: Department of Microbiology and Immunology, Chicago Medical School, Ro- of Pharmacology, University of California, San Diego, La Jolla, CA 92093; Moores salind Franklin University of Medicine and Science, 3333 Green Bay Road, North Cancer Center, University of California, San Diego, La Jolla, CA 92093; and #Sanford Chicago, IL 60088. E-mail address: [email protected] Consortium for Regenerative Medicine, La Jolla, CA 92037 The online version of this article contains supplemental material. 1Current address: Instituto de Biofı´sica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil. Abbreviations used in this article: AUC, area under the curve; Bcl6, B-cell CLL/lymphoma 6; ChIP-seq, chromatin immunoprecipitation followed by next generation sequencing; ORCIDs: 0000-0003-0178-3329 (G.J.M.); 0000-0002-6484-6262 (S.C.); 0000-0002- GC, germinal center; LCMV, lymphocytic choriomeningitis virus; RNA-seq, RNA 1870-1775 (A.R.) sequencing; Tfh, follicular CD4+ Th; WT, wild type. Received for publication August 19, 2015. Accepted for publication January 5, 2016. Ó This work was supported by National Institutes of Health Grants R01AI 109842 (to Copyright 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 A.R.), AI40127 (to A.R.), R01AI072543 (to S.C.), and U19 AI109976 (to S.C.); a www.jimmunol.org/cgi/doi/10.4049/jimmunol.1501841 2016 CUTTING EDGE: NFAT PROTEINS DRIVE TFH CELL GENERATION AND MAINTENANCE RNA sequencing and chromatin immunoprecipitation followed by next develop in response to acute viral infections, and KLRG1 generation sequencing data analyses expression is associated with highly polarized Th1 cells in Previously published human RNA sequencing (RNA-seq) data from Weinstein some contexts (20, 21). The increased KLRG1 expression on et al. (19) were used. The mouse homologs of genes differentially expressed NFAT-deficient cells suggests that, in the absence of NFATs, in Tfh versus non-Tfh cells were identified. NFAT1 chromatin immuno- the cells become even more polarized toward Th1 (Fig. 1F, precipitation followed by next generation sequencing (ChIP-seq) data for memory-like CD8+ T cells were from our previous report (2). 1G). In summary, our results suggest that NFAT family members have an important role in the generation or main- Statistics tenance of Tfh cells in vivo upon viral infection, without Statistical analyses were done using Prism 6.0 (GraphPad). The p values were which GC and antiviral Ab responses are defective. calculated using two-tailed unpaired Student t tests with a 95% confidence interval. T cell–intrinsic defect in Tfh cell generation in NFAT1,2-deficient Results and Discussion mice Reduced Tfh cells and GCs in NFAT1,2-deficient mice To assess CD4 T cell–intrinsic activities of NFAT1 and 2 2 We investigated the role of two NFAT family members, NFAT2, we generated Nfat1 / , Nfat2fl/fl Cd4-Cre CD45.1+ NFAT1 and NFAT2, in the generation of Tfh cells using SMARTA TCR transgenic mice. Naive SMARTA CD45.1+ 2 2 single- and double-deficient Nfat1 / , Nfat2fl/fl Cd4-Cre mice CD4+ T cells were transferred into congenic mice that were (2). The frequency of total B cells was not affected in these then infected with LCMV. Expansion of the adoptively mice (data not shown). The mice were infected with LCMV transferred cells and expression of the activation marker Downloaded from Armstrong strain, which causes an acute viral infection, and CD44 was similar between WT and NFAT1,2-deficient the frequency of GC B cells and Tfh cells were determined in SMARTA cells 8 d postinfection (Supplemental Fig.
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