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Differential Requirements for Tcf1 Long Isoforms in CD8+ and CD4+ T Cell Responses to Acute Viral Infection

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Differential Requirements for Tcf1 Long Isoforms in CD8 + and CD4+ T Cell Responses to Acute Viral Infection This information is current as Jodi A. Gullicksrud, Fengyin Li, Shaojun Xing, Zhouhao of September 26, 2021. Zeng, Weiqun Peng, Vladimir P. Badovinac, John T. Harty and Hai-Hui Xue J Immunol 2017; 199:911-919; Prepublished online 26 June 2017; doi: 10.4049/jimmunol.1700595 Downloaded from http://www.jimmunol.org/content/199/3/911 Supplementary http://www.jimmunol.org/content/suppl/2017/06/24/jimmunol.170059 Material 5.DCSupplemental http://www.jimmunol.org/ References This article cites 40 articles, 11 of which you can access for free at: http://www.jimmunol.org/content/199/3/911.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 26, 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 © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Differential Requirements for Tcf1 Long Isoforms in CD8+ and CD4+ T Cell Responses to Acute Viral Infection Jodi A. Gullicksrud,*,† Fengyin Li,* Shaojun Xing,* Zhouhao Zeng,‡ Weiqun Peng,‡ Vladimir P. Badovinac,*,†,x John T. Harty,*,† and Hai-Hui Xue*,† In response to acute viral infection, activated naive T cells give rise to effector T cells that clear the pathogen and memory T cells that persist long-term and provide heightened protection. T cell factor 1 (Tcf1) is essential for several of these differentiation processes. Tcf1 is expressed in multiple isoforms, with all isoforms sharing the same HDAC and DNA-binding domains and the long isoforms containing a unique N-terminal b-catenin–interacting domain. In this study, we specifically ablated Tcf1 long isoforms in mice, while retaining expression of Tcf1 short isoforms. During CD8+ T cell responses, Tcf1 long isoforms were dispensable for generating cytotoxic CD8+ effector T cells and maintaining memory CD8+ T cell pool size, but they contributed to optimal maturation of central memory CD8+ T cells and their optimal secondary expansion in a recall response. In contrast, Tcf1 long Downloaded from isoforms were required for differentiation of T follicular helper (TFH) cells, but not TH1 effectors, elicited by viral infection. Although Tcf1 short isoforms adequately supported Bcl6 and ICOS expression in TFH cells, Tcf1 long isoforms remained important for suppressing the expression of Blimp1 and TH1-associated genes and for positively regulating Id3 to restrain germinal center TFH cell differentiation. Furthermore, formation of memory TH1 and memory TFH cells strongly depended on Tcf1 long isoforms. These data reveal that Tcf1 long and short isoforms have distinct, yet complementary, functions and may represent an evolutionarily conserved means to ensure proper programming of CD8+ and CD4+ T cell responses to viral http://www.jimmunol.org/ infection. The Journal of Immunology, 2017, 199: 911–919. n response to a viral infection, naive T cells that recognize T cells predominantly differentiate into two types of effectors: their cognate Ags become activated, expand prolifically, and TH1 cells that secrete IFN-g and enhance the cytotoxicity of ef- + differentiate into effector T cells equipped with diverse fector CD8 T cells, and T follicular helper (TFH) cells that secrete I + functions. Effector CD8 T cells acquire cytotoxic functions and IL-4 and IL-21 and provide essential help to Ab-producing B cells eliminate virus-infected cells (1, 2). In contrast, activated CD4+ (3–5). Effector T cells are heterogeneous and contain subsets that have different kinetics of contraction following the peak responses by guest on September 26, 2021 and, hence, different potential to give rise to memory T cells. *Department of Microbiology, University of Iowa, Iowa City, IA 52242; Although memory CD8+ T cells are more durable than memory † Interdisciplinary Immunology Graduate Program, University of Iowa, Iowa City, CD4+ T cells, both populations contribute to enhanced responses IA 52242; ‡Department of Physics, The George Washington University, Washington, DC 20052; and xDepartment of Pathology, Carver College of Medicine, University of upon rechallenge with the same Ag. Iowa, Iowa City, IA 52242 Differentiation of effector T cells and their transition to memory ORCIDs: 0000-0003-0777-2196 (S.X.); 0000-0003-3180-2439 (V.P.B.); 0000-0001- T cells are coordinated by transcriptional regulators (5, 6). In 7266-2802 (J.T.H.); 0000-0002-9163-7669 (H.-H.X.). activated CD8+ T cells, T-bet and Blimp1 transcription factors, as Received for publication January 6, 2017. Accepted for publication June 7, 2017. well as the Id2 cofactor, are potently induced and critically reg- This work was supported by the National Institute of Health (Grants AI112579 and ulate CD8+ effector cell differentiation and acquisition of cyto- AI115149 to H.-H.X., Grant AI042767 to J.T.H., Grant AI119160 to H.-H.X. and V.P.B., Grants AI114543 and GM113961 to V.P.B., Grant AI121080 to H.-H.X. and W.P., toxic functions (7–9). In contrast, Eomes, Bcl6, and Id3 promote and Grant AI113806 to W.P.) and the U.S. Department of Veterans Affairs (Grant I01 the transition and survival of memory CD8+ T cells (9–11). In BX002903 to H.-H.X.). J.A.G. is the recipient of a University of Iowa Presidential + Graduate Research Fellowship, a T32 Predoctoral Training Grant in Immunology CD4 T cells, T-bet and Bcl6 are the lineage-specifying master (AI007485), and the Ballard and Seashore Dissertation Fellowship. The flow cytom- regulators for TH1 and TFH cells, respectively (3, 4), and induction etry core facility at the University of Iowa is supported by the Carver College of of Blimp1 and Id2 favors T 1 differentiation at the expense of the Medicine, the Holden Comprehensive Cancer Center, and the Iowa City Veteran’s H Administration Medical Center, as well as by grants from the National Cancer Insti- TFH lineage (12, 13). In contrast to advances in elucidating the tute (P30CA086862) and the National Center for Research Resources, National transcriptional networks in CD4+ lineage differentiation at the ef- Institutes of Health (S10 OD016199). fector phase, little is known about transcriptional regulation in- The RNA sequencing data presented in this article have been submitted to the Gene + Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/) under accession number volved in memory CD4 T cell formation and functions. GSE98347. T cell factor 1 (Tcf1) has been known as a transcription factor Address correspondence and reprint requests to Dr. Hai-Hui Xue, University of Iowa, acting downstream of the Wnt pathway and can interact with 51 Newton Road, BSB 3-772, Iowa City, IA 52242. E-mail address: hai-hui-xue@uiowa. b-catenin coactivator. b-catenin is posttranslationally regulated edu and stabilized by Wnt- or PG-derived signals. In addition to its The online version of this article contains supplemental material. essential role for T cell development (14, 15), recent studies have Abbreviations used in this article: dpi, day postinfection; GC, germinal center; revealed that Tcf1 critically regulates mature T cell responses. LCMV, lymphocytic choriomeningitis virus; LCMV-Arm, LCMV Armstrong strain; LCMV-Cl13, LCMV clone 13; LN, lymph node; RNA-Seq, RNA sequencing; Tcf1, Although loss of Tcf1 modestly diminished production of effector + T cell factor 1; TCM, central memory T; TEM, effector memory T; TFH, T follicular CD8 T cells, Tcf1 is essential for maturation, longevity, and helper; WT, wild-type. secondary expansion of memory CD8+ T cells (16, 17). In acti- + Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 vated CD4 T cells, Tcf1 appears to restrain TH1 differentiation www.jimmunol.org/cgi/doi/10.4049/jimmunol.1700595 912 Tcf1 LONG ISOFORMS IN MATURE T CELL RESPONSES + 3 4 + + in vitro (18) but is essential for activating the TFH program by characterization of CD8 T cell responses, 2 10 Va2 P14 CD8 + acting upstream of Bcl6 (12, 19, 20). As a result of differential T cells were injected i.v. into CD45.1 B6.SJL recipient mice and infected 3 5 promoter usage and alternative splicing, multiple Tcf1 isoforms can i.p. with 2 10 PFU lymphocytic choriomeningitis virus (LCMV) Armstrong strain (LCMV-Arm). For characterization of CD4+ T cell re- be detected in T cells (21). All isoforms contain a C-terminal HMG sponses, 2 3 105 Va2+ SMARTA CD4+ T cells were injected i.v. into DNA-binding domain, which can also interact with Groucho/ CD45.1+ hosts and infected similarly. For examining CD4+ T cell re- 2 2 2 transducin-like enhancer of split corepressor proteins, and a sponses under a competitive condition, 5000 p45+/ or p45 / SMARTA + newly discovered HDAC domain (22). The Tcf1 long isoforms (p45 CD4 T cells were mixed with the same number of wild-type (WT) CD45.1+CD45.2+ SMARTA CD4+ T cells and adoptively transferred. and p42) contain an N-terminal b-catenin–binding domain, whereas At $40 d postinfection (dpi), the immune mice were infected i.v. with 2 3 the Tcf1 short isoforms (p33 and p30) lack this domain and, hence, 106 PFU LCMV clone 13 (LCMV-Cl13) to elicit secondary CD8+ or CD4+ cannot interact with b-catenin.
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