The Transcription Factor IRF4 is Essential for TCR Affinity-mediated Metabolic Programming and Clonal Expansion of T Cells

Overview

Journal Nat Immunol

Date 2013 Sep 24

PMID 24056747

Citations 231

Authors

Kevin Man

Maria Miasari

Wei Shi

Annie Xin

Darren C Henstridge

Simon Preston

Marc Pellegrini

Gabrielle T Belz

Gordon K Smyth

Mark A Febbraio

Stephen L Nutt

Axel Kallies

Affiliations

Soon will be listed here.

Abstract

During immune responses, T cells are subject to clonal competition, which leads to the predominant expansion of high-affinity clones; however, there is little understanding of how this process is controlled. We found here that the transcription factor IRF4 was induced in a manner dependent on affinity for the T cell antigen receptor (TCR) and acted as a dose-dependent regulator of the metabolic function of activated T cells. IRF4 regulated the expression of key molecules required for the aerobic glycolysis of effector T cells and was essential for the clonal expansion and maintenance of effector function of antigen-specific CD8(+) T cells. Thus, IRF4 is an indispensable molecular 'rheostat' that 'translates' TCR affinity into the appropriate transcriptional programs that link metabolic function with the clonal selection and effector differentiation of T cells.

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References

Shoukry N, Grakoui A, Houghton M, Chien D, Ghrayeb J, Reimann K . Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection. J Exp Med. 2003; 197(12):1645-55. PMC: 2193956. DOI: 10.1084/jem.20030239. View

Gett A, Sallusto F, Lanzavecchia A, Geginat J . T cell fitness determined by signal strength. Nat Immunol. 2003; 4(4):355-60. DOI: 10.1038/ni908. View

Kerdiles Y, Beisner D, Tinoco R, Dejean A, Castrillon D, DePinho R . Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor. Nat Immunol. 2009; 10(2):176-84. PMC: 2856471. DOI: 10.1038/ni.1689. View

Finlay D, Rosenzweig E, Sinclair L, Feijoo-Carnero C, Hukelmann J, Rolf J . PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. J Exp Med. 2012; 209(13):2441-53. PMC: 3526360. DOI: 10.1084/jem.20112607. View

Rutishauser R, Martins G, Kalachikov S, Chandele A, Parish I, Meffre E . Transcriptional repressor Blimp-1 promotes CD8(+) T cell terminal differentiation and represses the acquisition of central memory T cell properties. Immunity. 2009; 31(2):296-308. PMC: 2783637. DOI: 10.1016/j.immuni.2009.05.014. View

Chang C, Curtis J, Maggi Jr L, Faubert B, Villarino A, OSullivan D . Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell. 2013; 153(6):1239-51. PMC: 3804311. DOI: 10.1016/j.cell.2013.05.016. View

Kallies A, Hasbold J, Tarlinton D, Dietrich W, Corcoran L, Hodgkin P . Plasma cell ontogeny defined by quantitative changes in blimp-1 expression. J Exp Med. 2004; 200(8):967-77. PMC: 2211847. DOI: 10.1084/jem.20040973. View

Kwon H, Thierry-Mieg D, Thierry-Mieg J, Kim H, Oh J, Tunyaplin C . Analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors. Immunity. 2010; 31(6):941-52. PMC: 3272079. DOI: 10.1016/j.immuni.2009.10.008. View

Seah S, Carrington E, Ng W, Belz G, Brady J, Sutherland R . Unlike CD4+ T-cell help, CD28 costimulation is necessary for effective primary CD8+ T-cell influenza-specific immunity. Eur J Immunol. 2012; 42(7):1744-54. DOI: 10.1002/eji.201142211. View

10.

Flynn K, Belz G, Altman J, Ahmed R, Woodland D, Doherty P . Virus-specific CD8+ T cells in primary and secondary influenza pneumonia. Immunity. 1998; 8(6):683-91. DOI: 10.1016/s1074-7613(00)80573-7. View

11.

Ciofani M, Madar A, Galan C, Sellars M, Mace K, Pauli F . A validated regulatory network for Th17 cell specification. Cell. 2012; 151(2):289-303. PMC: 3503487. DOI: 10.1016/j.cell.2012.09.016. View

12.

Sarkar S, Teichgraber V, Kalia V, Polley A, Masopust D, Harrington L . Strength of stimulus and clonal competition impact the rate of memory CD8 T cell differentiation. J Immunol. 2007; 179(10):6704-14. DOI: 10.4049/jimmunol.179.10.6704. View

13.

Day E, Carmichael A, Ten Berge I, Waller E, Sissons J, Wills M . Rapid CD8+ T cell repertoire focusing and selection of high-affinity clones into memory following primary infection with a persistent human virus: human cytomegalovirus. J Immunol. 2007; 179(5):3203-13. DOI: 10.4049/jimmunol.179.5.3203. View

14.

Zheng Y, Chaudhry A, Kas A, deRoos P, Kim J, Chu T . Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature. 2009; 458(7236):351-6. PMC: 2864791. DOI: 10.1038/nature07674. View

15.

Wu M, Neilson A, Swift A, Moran R, Tamagnine J, Parslow D . Multiparameter metabolic analysis reveals a close link between attenuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells. Am J Physiol Cell Physiol. 2006; 292(1):C125-36. DOI: 10.1152/ajpcell.00247.2006. View

16.

Leggatt G, Berzofsky J . Selective expansion of high- or low-avidity cytotoxic T lymphocytes and efficacy for adoptive immunotherapy. Proc Natl Acad Sci U S A. 1996; 93(9):4102-7. PMC: 39494. DOI: 10.1073/pnas.93.9.4102. View

17.

Wang R, Green D . Metabolic checkpoints in activated T cells. Nat Immunol. 2012; 13(10):907-15. DOI: 10.1038/ni.2386. View

18.

Cruz-Guilloty F, Pipkin M, Djuretic I, Levanon D, Lotem J, Lichtenheld M . Runx3 and T-box proteins cooperate to establish the transcriptional program of effector CTLs. J Exp Med. 2009; 206(1):51-9. PMC: 2626671. DOI: 10.1084/jem.20081242. View

19.

Hogquist K, Jameson S, Heath W, Howard J, Bevan M, Carbone F . T cell receptor antagonist peptides induce positive selection. Cell. 1994; 76(1):17-27. DOI: 10.1016/0092-8674(94)90169-4. View

20.

Staudt V, Bothur E, Klein M, Lingnau K, Reuter S, Grebe N . Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity. 2010; 33(2):192-202. DOI: 10.1016/j.immuni.2010.07.014. View