transcription factor Interferon Regulatory Factor 4 is required for the generation of protective effector CD8⁺ T cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 37; pp. 15019 - 15024
• Main Authors: Raczkowski, Friederike, Ritter, Josephine, Heesch, Kira, Schumacher, Valéa, Guralnik, Anna, Höcker, Lena, Raifer, Hartmann, Klein, Matthias, Bopp, Tobias, Harb, Hani, Kesper, Dörthe A., Pfefferle, Petra I., Grusdat, Melanie, Lang, Philipp A., Mittrücker, Hans-Willi, Huber, Magdalena
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 10.09.2013; National Acad Sciences
• Subjects: Animals; B lymphocytes; B-cell lymphoma; Biological Sciences; Cell Differentiation; Cell Proliferation; Cytokines; Gene Expression; Gene expression regulation; Genotype & phenotype; Host-Pathogen Interactions - genetics; Host-Pathogen Interactions - immunology; Immunity; Infections; Interferon Regulatory Factors - deficiency; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - immunology; Listeria; Listeria monocytogenes; Listeria monocytogenes - immunology; Listeriosis - genetics; Listeriosis - immunology; Listeriosis - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Phenotypes; Plasma cells; Positive Regulatory Domain I-Binding Factor 1; Proteins; Rodents; Spleen; T cell receptors; T lymphocytes; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism; T-Lymphocytes, Cytotoxic - pathology; Transcription factors; Transcription Factors - biosynthesis; Transcription Factors - genetics
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1309378110

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.