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. 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.

Heterogeneity in the Differentiation and Function of CD8+ T Cells

“…Whereas T-bet (Intlekofer et al 2005;Joshi et al 2007), Id2 (Cannarile et al 2006), Blimp-1 (Kallies et al 2009;Rutishauser et al 2009) and interferon regulatory factor (IRF)4 (Man et al 2013;Raczkowski et al 2013;Yao et al 2013) promote effector development, BCL-6 (Cui et al 2011;Ichii et al 2002), Eomesodermin (Eomes) (Intlekofer et al 2005), Id3 (Ji et al 2011;Yang et al 2011), TCF-7 (Zhou et al 2010) and Foxo1 (Hess Michelini et al 2013Kim et al 2013;Tejera et al 2013) are associated with memory-cell differentiation. Several signaling pathways induced by environmental cues regulate the expression of these transcriptional regulators.…”

“…Finally, the strength of T cell receptor (TCR) signaling plays pivotal role for differentiation of effector Tc1 cells and the transcription factor IRF4 was recently shown to be the central sensor translating signal strength into a transcriptional program (Man et al 2013;Raczkowski et al 2013;Yao et al 2013). Strong TCR signaling causes high expression of IRF4, while weak signals induce lower amounts of this transcription factor.…”

“…T cells, it is crucial for the sustained proliferation, survival and effector differentiation of Tc1 cells (Man et al 2013;Raczkowski et al 2013;Yao et al 2013). IRF4 fulfills these multiple effects by several means.…”

Haploinsufficiency of interferon regulatory factor 4 strongly protects against autoimmune diabetes in NOD mice

“…At the molecular level, studies have suggested that IRF4, together with BATF (basic leucine zipper transcription factor ATF-like) and the activator protein-1 family member JUN, acts as a 'pioneer transcriptional factor' that prepares chromatin accessibility for the subsequent lineage-specific transcriptional factor and drives gene expression for the differentiation of effector T cells [8][9][10]. It has been documented that IRF4 is necessary for the differentiation of diverse effector CD4 + T cell subsets, including helper T cell (Th) types 2 [11][12][13], Th9 [14] and Th17 [6,15,16], follicular Th cells [17], the sustained effector function of cytotoxic T cells [18][19][20], the regulation of effector regulatory T cells (Tregs) [21], the series of developmental stages of B cells [17,[22][23][24][25][26] and the development and function of dendritic cells (DCs) [27][28][29][30].…”

“…Studies have indicated that IRF4 is essential for sustaining the differentiation of CD8 + T cells by regulating transcriptional factors that are crucial for effector generation (T-bet and Blimp-1) [18,19]. Furthermore, the expression of IRF4, which is regulated by antigen-T cell receptor (TCR) affinity, has also been reported to be required for the metabolic function and migratory behaviour of activated CD8 + T cells in a dose-dependent manner [20].…”