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

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.