title: The transcription factor Interferon Regulatory Factor 4 is required for the generation of protective effector CD8+ T cells.
abstract: Robust cytotoxic CD8(+) T-cell response is important for immunity to intracellular pathogens. Here, we show that the transcription factor IFN Regulatory Factor 4 (IRF4) is crucial for the protective CD8(+) T-cell response to the intracellular bacterium Listeria monocytogenes. IRF4-deficient (Irf4(-/-)) mice could not clear L. monocytogenes infection and generated decreased numbers of L. monocytogenes-specific CD8(+) T cells with impaired effector phenotype and function. Transfer of wild-type CD8(+) T cells into Irf4(-/-) mice improved bacterial clearance, suggesting an intrinsic defect of CD8(+) T cells in Irf4(-/-) mice. Following transfer into wild-type recipients, Irf4(-/-) CD8(+) T cells became activated and showed initial proliferation upon L. monocytogenes infection. However, these cells could not sustain proliferation, produced reduced amounts of IFN-γ and TNF-α, and failed to acquire cytotoxic function. Forced IRF4 expression in Irf4(-/-) CD8(+) T cells rescued the defect. During acute infection, Irf4(-/-) CD8(+) T cells demonstrated diminished expression of B lymphocyte-induced maturation protein-1 (Blimp-1), inhibitor of DNA binding (Id)2, and T-box expressed in T cells (T-bet), transcription factors programming effector-cell generation. IRF4 was essential for expression of Blimp-1, suggesting that altered regulation of Blimp-1 contributes to the defects of Irf4(-/-) CD8(+) T cells. Despite increased levels of B-cell lymphoma 6 (BCL-6), Eomesodermin, and Id3, Irf4(-/-) CD8(+) T cells showed impaired memory-cell formation, indicating additional functions for IRF4 in this process. As IRF4 governs B-cell and CD4(+) T-cell differentiation, the identification of its decisive role in peripheral CD8(+) T-cell differentiation, suggests a common regulatory function for IRF4 in adaptive lymphocytes fate decision.
authors: Institute for Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors: Friederike
authors: F
authors: Raczkowski
authors: Josephine
authors: J
authors: Ritter
authors: Kira
authors: K
authors: Heesch
authors: Valéa
authors: V
authors: Schumacher
authors: Anna
authors: A
authors: Guralnik
authors: Lena
authors: L
authors: Höcker
authors: Hartmann
authors: H
authors: Raifer
authors: Matthias
authors: M
authors: Klein
authors: Tobias
authors: T
authors: Bopp
authors: Hani
authors: H
authors: Harb
authors: Dörthe A
authors: DA
authors: Kesper
authors: Petra I
authors: PI
authors: Pfefferle
authors: Melanie
authors: M
authors: Grusdat
authors: Philipp A
authors: PA
authors: Lang
authors: Hans-Willi
authors: HW
authors: Mittrücker
authors: Magdalena
authors: M
authors: Huber
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D015870:Gene Expression; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D050835:Interferon Regulatory Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074462:Positive Regulatory Domain I-Binding Factor 1; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1; D014157:Transcription Factors; D000099218:Interferon Regulatory Factor-4; C513258:Prdm1 protein, mouse
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