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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We thank T.W. Mak (Campbell Family Cancer Research Institute) for Irf4−/− mice; U. Klein (Columbia University) for mice with loxP-flanked Irf4 alleles; S.M. Kaech (Yale University School of Medicine) for mice expressing Cre under the control of Gzmb; P. Bouillet (The Walter and Eliza Hall Institute) for Bim−/− mice; S. Cory (The Walter and Eliza Hall Institute) for mice with transgenic overexpression of Bcl-2 in all hematopoietic cells (Vav-Bcl2tg mice); D. Zehn (Swiss Vaccine Research Institute) for OVA-expressing L. monocytogenes variants; A.M. Lew (The Walter and Eliza Hall Institute) for HKx31-OVA; S. Sterle, R. Cole, N. Iannarella and L. Mackiewicz for technical support; and D. Segal, P.D. Hodgkin, L.M. Corcoran, S. Heinzel, F. Masson (all The Walter and Eliza Hall Institute) and C. Palmer (Burnet Institute) for antibodies and discussions. Supported by the National Health and Medical Research Council of Australia (M.P., G.T.B., G.K.S., S.L.N., M.A.F. and A.K.), the Sylvia and Charles Viertel Foundation (A.K. and G.T.B.), the Howard Hughes Medical Institute (G.T.B.), the Australian Research Council (S.L.N. and A.K.), the National Heart Foundation (D.C.H.) and The Walter and Eliza Hall Institute Genomics Fund (A.K., G.T.B. and W.S.), the Victorian State Government Operational Infrastructure Support and Australian Government National Health and Medical Research Council Independent Research Institute Infrastructure Support scheme.
The authors declare no competing financial interests.
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Man, K., Miasari, M., Shi, W. et al. The transcription factor IRF4 is essential for TCR affinity–mediated metabolic programming and clonal expansion of T cells. Nat Immunol 14, 1155–1165 (2013). https://doi.org/10.1038/ni.2710
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