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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 11551165 (2013) | Download Citation


  • A Corrigendum to this article was published on 19 August 2014

This article has been updated


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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Change history

  • 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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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.

Author information


  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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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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Axel Kallies.

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