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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, John T. Harty and Hai-Hui Xue
J Immunol June 26, 2017, ji1700595; DOI: https://doi.org/10.4049/jimmunol.1700595
Jodi A. Gullicksrud
*Department of Microbiology, University of Iowa, Iowa City, IA 52242;
†Interdisciplinary Immunology Graduate Program, University of Iowa, Iowa City, IA 52242;
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Fengyin Li
*Department of Microbiology, University of Iowa, Iowa City, IA 52242;
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Shaojun Xing
*Department of Microbiology, University of Iowa, Iowa City, IA 52242;
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Zhouhao Zeng
‡Department of Physics, The George Washington University, Washington, DC 20052; and
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Weiqun Peng
‡Department of Physics, The George Washington University, Washington, DC 20052; and
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Vladimir P. Badovinac
*Department of Microbiology, University of Iowa, Iowa City, IA 52242;
†Interdisciplinary Immunology Graduate Program, University of Iowa, Iowa City, IA 52242;
§Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
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John T. Harty
*Department of Microbiology, University of Iowa, Iowa City, IA 52242;
†Interdisciplinary Immunology Graduate Program, University of Iowa, Iowa City, IA 52242;
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Hai-Hui Xue
*Department of Microbiology, University of Iowa, Iowa City, IA 52242;
†Interdisciplinary Immunology Graduate Program, University of Iowa, Iowa City, IA 52242;
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Abstract

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 β-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 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 infection.

Footnotes

  • This work was supported by the National Institute of Health (Grants AI112579 and 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., and Grant AI113806 to W.P.) and the U.S. Department of Veterans Affairs (Grant I01 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 (AI007485), and the Ballard and Seashore Dissertation Fellowship. The flow cytometry core facility at the University of Iowa is supported by the Carver College of Medicine, the Holden Comprehensive Cancer Center, and the Iowa City Veteran’s Administration Medical Center, as well as by grants from the National Cancer Institute (P30CA086862) and the National Center for Research Resources, National Institutes of Health (S10 OD016199).

  • 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 GSE98347.

  • The online version of this article contains supplemental material.

  • Received January 6, 2017.
  • Accepted June 7, 2017.
  • Copyright © 2017 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 206 (5)
The Journal of Immunology
Vol. 206, Issue 5
1 Mar 2021
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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, John T. Harty, Hai-Hui Xue
The Journal of Immunology June 26, 2017, ji1700595; DOI: 10.4049/jimmunol.1700595

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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, John T. Harty, Hai-Hui Xue
The Journal of Immunology June 26, 2017, ji1700595; DOI: 10.4049/jimmunol.1700595
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