Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses.
In the course of infection or autoimmunity, particular transcription factors orchestrate the differentiation of T(H)1, T(H)2 or T(H)17 effector cells, the responses of which are limited by a distinct lineage of suppressive regulatory T cells (T(reg)). T(reg) cell differentiation and function are guided by the transcription factor Foxp3, and their deficiency due to mutations in Foxp3 results in aggressive fatal autoimmune disease associated with sharply augmented T(H)1 and T(H)2 cytokine production. Recent studies suggested that Foxp3 regulates the bulk of the Foxp3-dependent transcriptional program indirectly through a set of transcriptional regulators serving as direct Foxp3 targets. Here we show that in mouse T(reg) cells, high amounts of interferon regulatory factor-4 (IRF4), a transcription factor essential for T(H)2 effector cell differentiation, is dependent on Foxp3 expression. We proposed that IRF4 expression endows T(reg) cells with the ability to suppress T(H)2 responses. Indeed, ablation of a conditional Irf4 allele in T(reg) cells resulted in selective dysregulation of T(H)2 responses, IL4-dependent immunoglobulin isotype production, and tissue lesions with pronounced plasma cell infiltration, in contrast to the mononuclear-cell-dominated pathology typical of mice lacking T(reg) cells. Our results indicate that T(reg) cells use components of the transcriptional machinery, promoting a particular type of effector CD4(+) T cell differentiation, to efficiently restrain the corresponding type of the immune response.
Zheng
Ye
Y
Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA.
Chaudhry
Ashutosh
A
Kas
Arnold
A
deRoos
Paul
P
Kim
Jeong M
JM
Chu
Tin-Tin
TT
Corcoran
Lynn
L
Treuting
Piper
P
Klein
Ulf
U
Rudensky
Alexander Y
AY
D000818:Animals; D001327:Autoimmune Diseases / Q000473:pathology; D018791:CD4 Lymphocyte Count; D002454:Cell Differentiation; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D050835:Interferon Regulatory Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology; D000099218:Interferon Regulatory Factor-4
D051858:Forkhead Transcription Factors; D007073:Immunoglobulin E; D007074:Immunoglobulin G; D050835:Interferon Regulatory Factors; D000099218:Interferon Regulatory Factor-4; C498833:Foxp3 protein, mouse