The transcription factor interferon regulatory factor 4 is required for the generation of protective effector CD8+ T cells

Friederike Raczkowski, Josephine Ritter, Kira Heesch, Valéa Schumacher, Anna Guralnik, Lena Höcker, Hartmann Raifer, Matthias Klein, Tobias Bopp, Hani Harb, Dörthe A. Kesper, Petra I. Pfefferle, Melanie Grusdat, Philipp A. Lang, Hans Willi Mittrücker*, Magdalena Huber

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

66 Citations (Scopus)

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. monocytogenesspecific 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.

Original languageEnglish
Pages (from-to)15019-15024
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number37
DOIs
Publication statusPublished - 10 Sep 2013
Externally publishedYes

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