© 2013 Nature America, Inc. All rights reserved. NATURE IMMUNOLOGY ADVANCE ONLINE PUBLICATION 1 ARTICLES T cell responses are guided by multiple cell-extrinsic cues, includ- ing antigens, costimulatory molecules and cytokines, which lead to the induction of transcriptional regulators that ultimately control the differentiation of activated T cells into effector and memory T cells. Several critical transcriptional regulators and some of their down- stream targets involved in this process have been identified 1,2 . The best-known transcription factors that control CD8 + T cell differentia- tion in the periphery are the T-box transcription factors T-bet and Eomes, which act in concert during the differentiation of effector and memory T cells 3 . In addition, the transcription factor Blimp-1 has been found to drive the terminal differentiation of short-lived cyto- toxic effector T cells at the expense of memory T cells 4,5 , and opposing activities of transcription factors Id2 and Id3, which antagonize the DNA-binding activity of E-proteins, have been identified 6,7 . The interaction between an antigen and its cognate T cell anti- gen receptor (TCR) is a critical determinant of the outcome of T cell responses 8 . Whereas the early phase of T cell responses is char- acterized by the proliferation of a diverse array of antigen-specific clones with a broad range of affinities for the antigen-derived peptide epitopes, the later phase is dominated by a limited number of clones, in particular those with higher affinities. Such ‘focusing’ of the T cell response is the result of clonal competition and leads to the establish- ment of dominant epitope–specific T cell clones of high affinity 9–13 that are critical for the control of pathogens 14–16 . Recruitment, pro- liferation and acquisition of effector function are similar for CD8 + T cells responding to a high-affinity antigen and those responding to a low-affinity antigen 17 . However, T cells responding to a low-affinity antigen fail to accumulate during infection and thus contribute only minimally to the effector population at the peak of the response 17 . Differences in migration and survival 17–19 or ‘diversion’ into mem- ory 20–22 have been linked to the diminished population expan- sion of CD8 + T cells stimulated with a low-affinity antigen. Thus, differences in the clonal expansion of T cells are the consequence of multiple effects, including proliferation and cell death. Nonetheless, it has remained unclear how TCR signals that result from interactions with ligands of various affinities are ‘translated’ into distinct tran- scriptional programs and differentiation outcomes. The transcription factor IRF4 is required for various functions in the immune system 23 , including the differentiation of plasma cells 24,25 , the function of regulatory T cells 26,27 and the development of several CD4 + helper T cell subsets 28–30 . Its role in the differentiation and function of cytotoxic effector T cells, however, has not been examined in any detail. We found here that IRF4-deficient mice failed to mount a productive CD8 + T cell response during viral or bacterial challenge. IRF4 was required for ongoing expansion of antigen-specific CD8 + T cell clones and for the maintenance of effector functions. We estab- lished that IRF4 expression was strictly controlled by TCR affinity and that IRF4 acted in a dose-dependent manner to promote the ‘prefer- ential’ expansion of high-affinity T cell clones. Finally, we found that IRF4 was a key regulator of the metabolic function of effector CD8 + T cells whose ‘graded’ expression determined the amount of aero- bic glycolysis after T cell activation. Thus, our data lead to a model in which IRF4 occupies the center of a transcriptional network that controls metabolic programming and underlies the affinity selection, 1 The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia. 2 The Department of Medical Biology, University of Melbourne, Parkville, Australia. 3 The Department of Computing and Information Systems, University of Melbourne, Parkville, Australia. 4 Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Australia. 5 The Department of Mathematics and Statistics, University of Melbourne, Parkville, Australia. Correspondence should be addressed to A.K. (kallies@wehi.edu.au). Received 26 June; accepted 13 August; published online 22 September 2013; doi:10.1038/ni.2710 The transcription factor IRF4 is essential for TCR affinity–mediated metabolic programming and clonal expansion of T cells Kevin Man 1,2 , Maria Miasari 1,2 , Wei Shi 1,3 , Annie Xin 1,2 , Darren C Henstridge 4 , Simon Preston 1,2 , Marc Pellegrini 1,2 , Gabrielle T Belz 1,2 , Gordon K Smyth 1,5 , Mark A Febbraio 4 , Stephen L Nutt 1,2 & Axel Kallies 1,2 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.