The transcription factor IRF4 is essential for TCR affinity-mediated metabolic programming and clonal expansion of T cells.
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.
1] The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia. [2] The Department of Medical Biology, University of Melbourne, Parkville, Australia.
Kevin
K
Man
Maria
M
Miasari
Wei
W
Shi
Annie
A
Xin
Darren C
DC
Henstridge
Simon
S
Preston
Marc
M
Pellegrini
Gabrielle T
GT
Belz
Gordon K
GK
Smyth
Mark A
MA
Febbraio
Stephen L
SL
Nutt
Axel
A
Kallies
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D002454:Cell Differentiation; D049109:Cell Proliferation; D002999:Clone Cells; D005786:Gene Expression Regulation; D006801:Humans; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D014158:Transcription, Genetic; D000099218:Interferon Regulatory Factor-4
D050835:Interferon Regulatory Factors; D011948:Receptors, Antigen, T-Cell; D000099218:Interferon Regulatory Factor-4