Tcf1 at the crossroads of CD4<sup>+</sup> and CD8<sup>+</sup> T cell identity

doi:10.1007/s11515-017-1445-3

Front. Biol.

2017, Vol. 12

Issue (2) : 83-93 https://doi.org/10.1007/s11515-017-1445-3

REVIEW

Tcf1 at the crossroads of CD4⁺ and CD8⁺ T cell identity

Jodi A. Gullicksrud^1,², Qiang Shan¹(

), Hai-Hui Xue^1,²(

)

¹. Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
². Interdisciplinary Immunology Graduate Program, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA

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Abstract

Transcription factors and DNA/histone modification enzymes work in concert to establish and maintain cell identity. CD4⁺ and CD8⁺ T cells are key players in cellular immunity with distinct functions. Recent studies offer novel insights into how their identities are established in the thymus and maintained in the periphery during immune responses. During thymic maturation, Thpok, HDAC1 and HDAC2 guard CD4⁺ T cells from activation of CD8⁺ cytotoxic genes, and Tcf1 and Lef1 utilize their intrinsic HDAC activity to shut down CD4⁺ lineage-associated genes in CD8⁺ T cells. In activated CD4⁺ T cells, Tcf1 and Lef1 act upstream of the Bcl6-Blimp1 axis to direct differentiation of follicular helper T (Tfh) cells, and prevent diversion of Tfh to IL-17-producing cells. In parallel, T-bet, together with Eomes or Blimp1, ensures proper induction of the cytotoxic program in CD8⁺ effectors elicited by acute infection, and prevents generation of pathogenic, IL-17-producing CD8⁺ effector T cells. Antigen persistence due to chronic viral infection leads to CD8⁺ T cell exhaustion. A portion of exhausted CD8⁺ T cells has the capacity to activate the Tfh program in a Tcf1-dependent manner. Those Tfh-like CD8⁺ T cells exhibit enhanced proliferative capacity in response to PD-1 blockage therapy and are more effective in curtailing viral replication. Thus, dissecting the molecular aspects of T cell identity, during development and immune responses, may lead to new therapies for treating autoimmunity, tumors, and persistent infections.

Keywords Tcf1 Lef1 HDAC CD4⁺ T cells CD8⁺ T cells cell identity

Corresponding Author(s): Qiang Shan,Hai-Hui Xue

Online First Date: 20 March 2017 Issue Date: 14 April 2017

Cite this article:

Jodi A. Gullicksrud,Qiang Shan,Hai-Hui Xue. Tcf1 at the crossroads of CD4⁺ and CD8⁺ T cell identity[J]. Front. Biol., 2017, 12(2): 83-93.

URL:

https://academic.hep.com.cn/fib/EN/10.1007/s11515-017-1445-3
https://academic.hep.com.cn/fib/EN/Y2017/V12/I2/83

Fig.1 Diagram showing the functional structure of Tcf1 and Lef1 proteins. βBD, β-catenin binding domain; HDAC, histone deacetylase activity domain; HMG, high mobility group DNA binding domain. The numbers denote boundaries of highlighted functional domains based on the full length Tcf1 protein.

Fig.2 Tcf1 and Lef1 regulate CD4⁺ lineage choice by acting upstream of Thpok. TCRβ⁺ post-select thymocytes were analyzed in control, Tcf7^–/–, Lef1^–/–, and Tcf7^–/–Lef1^–/– mice on β2m^–/– background. (A) Immature (top) and mature (bottom) post-select thymocytes were analyzed for CD4 and CD8 expression. Immature cells contained DP, CD4⁺CD8^lo intermediates, CD4⁺ and CD8⁺ subsets, and mature cells contain CD4⁺, CD8⁺ subsets, and an additional CD4⁺CD8⁺ subset in Tcf7^–/– and Tcf7^–/–Lef1^–/– mice. Percentage of each subset is marked in representative contour plots from≥3 experiments (n≥5). (B) The expression of Thpok and Runx3 genes in TCRβ⁺ post-select DP thymocytes sorted from β2m^–/– and Tcf7^–/–Lef1^–/–β2m^–/– mice, as determined by qRT-PCR. The expression of each gene in β2m^–/– control cells is set as 1, and that in Tcf7^–/–Lef1^–/–β2m^–/– cells was normalized accordingly. Runx3d denotes a Runx3 transcript from CD8⁺ lineage-specific distal promoter. Data are means±s.d. from 3 experiments (n = 3 for β2m^–/–, and n = 6 for Tcf7^–/–Lef1^–/–β2m^–/–). p values were determined by Student’s t-test.

Fig.3 Conserved regulatory circuits upstream of the Tfh program. Regulatory roles of each transcription factor/regulator (in boxes) are observed in both CD4⁺ Tfh cells (generated in response to acute infection) and Tfh-like CXCR5⁺CD8⁺ cells (generated in response to chronic viral infection). Arrows denote positive regulation, lines ending in bars denote negative regulation, and dotted line marks indirect regulation.

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