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The transcription factor IRF4 is essential for TCR affinity–mediated metabolic programming and clonal expansion of T cells

Nature Immunology volume 14, pages 1155–1165 (2013)Cite this article

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A Corrigendum to this article was published on 19 August 2014

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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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Figure 1: IRF4 is essential for a productive CD8+ T cell response.
Figure 2: IRF4 in CD8+ T cells is not required for activation, proliferation or expression of effector molecules but is required for the prevention of cell death.
Figure 3: IRF4 is dispensable for the early proliferation and effector molecule expression of T cells in vivo but is required for ongoing clonal expansion and maintenance of effector function in a dose-dependent manner.
Figure 4: IRF4 expression and T cell population expansion is TCR affinity dependent.
Figure 5: IRF4 regulates the affinity-driven transcriptional program in CD8+ T cells.
Figure 6: IRF4-binding sites in genes encoding molecules involved in regulating effector and metabolic functions of CD8+ T cells.
Figure 7: IRF4 regulates the metabolic function of CD8+ T cells.
Figure 8: IRF4 regulates metabolic function of CD8+ T cells in vivo and can 'rescue' low-affinity T cell responses.

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  • 08 January 2014

    In the version of this article initially published, the scale of the top row (Naive) for S1pr1 in Figure 5d is incorrect. With the correct scale, S1pr1 expression in naive CD8+ T cells is accurately presented as very high. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

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.

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Authors and Affiliations

  1. The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

    Kevin Man, Maria Miasari, Wei Shi, Annie Xin, Simon Preston, Marc Pellegrini, Gabrielle T Belz, Gordon K Smyth, Stephen L Nutt & Axel Kallies

  2. The Department of Medical Biology, University of Melbourne, Parkville, Australia

    Kevin Man, Maria Miasari, Annie Xin, Simon Preston, Marc Pellegrini, Gabrielle T Belz, Stephen L Nutt & Axel Kallies

  3. The Department of Computing and Information Systems, University of Melbourne, Parkville, Australia

    Wei Shi

  4. Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Australia

    Darren C Henstridge & Mark A Febbraio

  5. The Department of Mathematics and Statistics, University of Melbourne, Parkville, Australia

    Gordon K Smyth

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Contributions

K.M. designed, did and analyzed most experiments; M.M., A.X. and D.C.H. did and analyzed experiments; S.P. and M.P. did and designed LCMV experiments; W.S. and G.K.S. did the bioinformatics analysis; G.T.B., M.A.F. and S.L.N. helped to design experiments and write the manuscript; and A.K. oversaw and designed the study and experiments, analyzed data and wrote the manuscript.

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Correspondence to Axel Kallies.

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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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