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

Subjects

A Corrigendum to this article was published on 19 August 2014

This article has been updated

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

Accession codes

Primary accessions

Gene Expression Omnibus

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.

References

  1. 1

    Belz, G.T. & Kallies, A. Effector and memory CD8+ T cell differentiation: toward a molecular understanding of fate determination. Curr. Opin. Immunol. 22, 279–285 (2010).

    CAS  PubMed  Google Scholar 

  2. 2

    Kaech, S.M. & Cui, W. Transcriptional control of effector and memory CD8+ T cell differentiation. Nat. Rev. Immunol. 12, 749–761 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Intlekofer, A.M. et al. Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin. Nat. Immunol. 6, 1236–1244 (2005).

    CAS  PubMed  Google Scholar 

  4. 4

    Kallies, A., Xin, A., Belz, G.T. & Nutt, S.L. Blimp-1 transcription factor is required for the differentiation of effector CD8+ T cells and memory responses. Immunity 31, 283–295 (2009).

    CAS  PubMed  Google Scholar 

  5. 5

    Rutishauser, R.L. et al. Transcriptional repressor Blimp-1 promotes CD8+ T cell terminal differentiation and represses the acquisition of central memory T cell properties. Immunity 31, 296–308 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Yang, C.Y. et al. The transcriptional regulators Id2 and Id3 control the formation of distinct memory CD8+ T cell subsets. Nat. Immunol. 12, 1221–1229 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Cannarile, M.A. et al. Transcriptional regulator Id2 mediates CD8+ T cell immunity. Nat. Immunol. 7, 1317–1325 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Gett, A.V., Sallusto, F., Lanzavecchia, A. & Geginat, J. T cell fitness determined by signal strength. Nat. Immunol. 4, 355–360 (2003).

    CAS  PubMed  Google Scholar 

  9. 9

    Day, E.K. et al. 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. 179, 3203–3213 (2007).

    CAS  PubMed  Google Scholar 

  10. 10

    Price, D.A. et al. Avidity for antigen shapes clonal dominance in CD8+ T cell populations specific for persistent DNA viruses. J. Exp. Med. 202, 1349–1361 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Malherbe, L., Hausl, C., Teyton, L. & McHeyzer-Williams, M.G. Clonal selection of helper T cells is determined by an affinity threshold with no further skewing of TCR binding properties. Immunity 21, 669–679 (2004).

    CAS  PubMed  Google Scholar 

  12. 12

    Busch, D.H. & Pamer, E.G. T cell affinity maturation by selective expansion during infection. J. Exp. Med. 189, 701–710 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Savage, P.A., Boniface, J.J. & Davis, M.M. A kinetic basis for T cell receptor repertoire selection during an immune response. Immunity 10, 485–492 (1999).

    CAS  Google Scholar 

  14. 14

    Alexander-Miller, M.A., Leggatt, G.R. & Berzofsky, J.A. Selective expansion of high- or low-avidity cytotoxic T lymphocytes and efficacy for adoptive immunotherapy. Proc. Natl. Acad. Sci. USA 93, 4102–4107 (1996).

    CAS  PubMed  Google Scholar 

  15. 15

    Schmitz, J.E. et al. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 283, 857–860 (1999).

    CAS  Google Scholar 

  16. 16

    Shoukry, N.H. et al. Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection. J. Exp. Med. 197, 1645–1655 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Zehn, D., Lee, S.Y. & Bevan, M.J. Complete but curtailed T-cell response to very low-affinity antigen. Nature 458, 211–214 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    King, C.G. et al. T cell affinity regulates asymmetric division, effector cell differentiation, and tissue pathology. Immunity 37, 709–720 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Wensveen, F.M. et al. Apoptosis threshold set by Noxa and Mcl-1 after T cell activation regulates competitive selection of high-affinity clones. Immunity 32, 754–765 (2010).

    CAS  PubMed  Google Scholar 

  20. 20

    Teixeiro, E. et al. Different T cell receptor signals determine CD8+ memory versus effector development. Science 323, 502–505 (2009).

    CAS  PubMed  Google Scholar 

  21. 21

    Smith-Garvin, J.E. et al. T-cell receptor signals direct the composition and function of the memory CD8+ T-cell pool. Blood 116, 5548–5559 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Sarkar, S. et al. Strength of stimulus and clonal competition impact the rate of memory CD8 T cell differentiation. J. Immunol. 179, 6704–6714 (2007).

    CAS  PubMed  Google Scholar 

  23. 23

    Mittrücker, H.W. et al. Requirement for the transcription factor LSIRF/IRF4 for mature B and T lymphocyte function. Science 275, 540–543 (1997).

    PubMed  Google Scholar 

  24. 24

    Klein, U. et al. Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination. Nat. Immunol. 7, 773–782 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Sciammas, R. et al. Graded expression of interferon regulatory factor-4 coordinates isotype switching with plasma cell differentiation. Immunity 25, 225–236 (2006).

    CAS  Google Scholar 

  26. 26

    Zheng, Y. et al. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 458, 351–356 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Cretney, E. et al. The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells. Nat. Immunol. 12, 304–311 (2011).

    CAS  Google Scholar 

  28. 28

    Brüstle, A. et al. The development of inflammatory TH-17 cells requires interferon-regulatory factor 4. Nat. Immunol. 8, 958–966 (2007).

    PubMed  Google Scholar 

  29. 29

    Staudt, V. et al. Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity 33, 192–202 (2010).

    CAS  Google Scholar 

  30. 30

    Kwon, H. et al. Analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors. Immunity 31, 941–952 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Jacob, J. & Baltimore, D. Modelling T-cell memory by genetic marking of memory T cells in vivo. Nature 399, 593–597 (1999).

    CAS  PubMed  Google Scholar 

  32. 32

    Ogilvy, S. et al. Constitutive Bcl-2 expression throughout the hematopoietic compartment affects multiple lineages and enhances progenitor cell survival. Proc. Natl. Acad. Sci. USA 96, 14943–14948 (1999).

    CAS  PubMed  Google Scholar 

  33. 33

    Bouillet, P. et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 286, 1735–1738 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Hogquist, K.A. et al. T cell receptor antagonist peptides induce positive selection. Cell 76, 17–27 (1994).

    CAS  Google Scholar 

  35. 35

    Seah, S.G. et al. Unlike CD4+ T-cell help, CD28 costimulation is necessary for effective primary CD8+ T-cell influenza-specific immunity. Eur. J. Immunol. 42, 1744–1754 (2012).

    CAS  PubMed  Google Scholar 

  36. 36

    Gronski, M.A. et al. TCR affinity and negative regulation limit autoimmunity. Nat. Med. 10, 1234–1239 (2004).

    CAS  PubMed  Google Scholar 

  37. 37

    Cruz-Guilloty, F. et al. Runx3 and T-box proteins cooperate to establish the transcriptional program of effector CTLs. J. Exp. Med. 206, 51–59 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Kerdiles, Y.M. et al. Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor. Nat. Immunol. 10, 176–184 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Rao, R.R., Li, Q., Gubbels Bupp, M.R. & Shrikant, P.A. Transcription factor Foxo1 represses T-bet-mediated effector functions and promotes memory CD8+ T cell differentiation. Immunity 36, 374–387 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Finlay, D.K. et al. PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. J. Exp. Med. 209, 2441–2453 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Li, P. et al. BATF-JUN is critical for IRF4-mediated transcription in T cells. Nature 490, 543–546 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Ciofani, M. et al. A validated regulatory network for Th17 cell specification. Cell 151, 289–303 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Glasmacher, E. et al. A genomic regulatory element that directs assembly and function of immune-specific AP-1-IRF complexes. Science 338, 975–980 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    MacIver, N.J., Michalek, R.D. & Rathmell, J.C. Metabolic regulation of T lymphocytes. Annu. Rev. Immunol. 31, 259–283 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Finlay, D. & Cantrell, D.A. Metabolism, migration and memory in cytotoxic T cells. Nat. Rev. Immunol. 11, 109–117 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    van der Windt, G.J. & Pearce, E.L. Metabolic switching and fuel choice during T-cell differentiation and memory development. Immunol. Rev. 249, 27–42 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Wang, R. & Green, D.R. Metabolic checkpoints in activated T cells. Nat. Immunol. 13, 907–915 (2012).

    CAS  Google Scholar 

  48. 48

    Wang, R. et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35, 871–882 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Chang, C.H. et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153, 1239–1251 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Tothova, Z. et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325–339 (2007).

    CAS  Google Scholar 

  51. 51

    Kallies, A. et al. Plasma cell ontogeny defined by quantitative changes in Blimp-1 expression. J. Exp. Med. 200, 967–977 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Flynn, K.J. et al. Virus-specific CD8+ T cells in primary and secondary influenza pneumonia. Immunity 8, 683–691 (1998).

    CAS  PubMed  Google Scholar 

  53. 53

    Belz, G.T., Xie, W., Altman, J.D. & Doherty, P.C. A previously unrecognized H-2Db-restricted peptide prominent in the primary influenza A virus-specific CD8+ T-cell response is much less apparent following secondary challenge. J. Virol. 74, 3486–3493 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Ritchie, R.H. et al. Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes. Diabetologia 55, 3369–3381 (2012).

    CAS  PubMed  Google Scholar 

  55. 55

    Wu, M. et al. 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. 292, C125–C136 (2007).

    CAS  Google Scholar 

  56. 56

    Liao, Y., Smyth, G.K. & Shi, W. The Subread aligner: fast, accurate and scalable read mapping by seed-and-vote. Nucleic Acids Res. 41, e108 (2013).

    PubMed  PubMed Central  Google Scholar 

  57. 57

    Zhang, Y. et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008).

    PubMed  PubMed Central  Google Scholar 

  58. 58

    Gentleman, R.C. et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 5, R80 (2004).

    PubMed  PubMed Central  Google Scholar 

  59. 59

    Smyth, G.K. in Bioinformatics and Computational Biology Solutions using R and Bioconductor (eds. Gentleman, R., Carey, V., Dudoit, S., Irizarry R. & Huber, W.) 397–420 (Springer, New York, 2005).

  60. 60

    Smyth, G.K. Linear models and empirical Bayes methods for assessing differential expression in microarray experiments. Stat. Appl. Genet. Mol. Biol. 3 issue 1, article 3 (2004).

    Google Scholar 

Download references

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.

Author information

Affiliations

Authors

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.

Corresponding author

Correspondence to Axel Kallies.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 and Supplementary Tables 1 and 2 (PDF 9182 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing