The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells

Cretney, Erika; Xin, Annie; Shi, Wei; Minnich, Martina; Masson, Frédérick; Miasari, Maria; Belz, Gabrielle T.; Smyth, Gordon K.; Busslinger, Meinrad; Nutt, Stephen L.; Kallies, Axel

doi:10.1038/ni.2006

Cited by 537 publications

(595 citation statements)

References 62 publications

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“…Accordingly, IRF4 specifically bound to the IL-21 responsive element and other regulatory regions of the Prdm1 gene. Recently, IRF4 was shown to be crucial in IL-21-induced Blimp-1 expression in B cells and CD4 + T cells (30) as well as in Treg cells (31). Our data extend these observations to CD8 + T cells and suggest the IRF4-Blimp-1 axis as a common regulatory mechanism in lymphocytes.…”

Section: Discussionsupporting

confidence: 77%

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

Raczkowski

Ritter

Heesch

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Section: Discussionsupporting

confidence: 77%

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

Raczkowski

Ritter

Heesch

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…When the expression of Treg-associated genes was inspected, we observed a comparably high expression of Ikzf4 (Eos), Ikzf2 (Helios), Nrp1, Il2ra (CD25), and Tnfrsf18 (GITR) in Foxp3 þ RORgt þ T cells and Foxp3 þ Tregs (Figure 2d). In addition, Foxp3 þ RORgt þ T cells displayed a uniquely high expression of genes that were recently associated with Treg populations resident in mucosal tissues, 9,27 including Il10, Gzmb, Prdm1 (Blimp-1), Itgae (CD103), Ctla4, and Icos (Figure 2e). This was in accordance with an activated CD44 int/high CD62L low phenotype, high CD25 surface expression, and increased ICOS levels as determined by fluorescence-activated cell sorting (FACS) analysis in mLNs and colon (Supplementary Figure S2).…”

Section: Resultsmentioning

confidence: 99%

“…Intriguingly, Foxp3 þ RORgt þ T cells showed high expression of Irf4, Prdm1, and Il10. In a recent report, Cretney et al 27 demonstrated that Blimp-1 (encoded by Prdm1) expression was restricted to a population of effector Tregs. Furthermore, they could show that Blimp-1 and IRF4 acted together to induce IL-10 expression.…”

Section: Discussionmentioning

confidence: 99%

Foxp3+ T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation

et al. 2016

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“…eT reg were found in LN during allograft responses, indicating that the suppressor function of T reg is mediated by this particular subset during inflammation. eT reg develop from T reg after TCR engagement in the presence of inflammatory cytokines (45). It remains to be tested whether IL-7R signaling promotes eT reg differentiation from cT reg or whether eT reg accumulate in the dLN by proliferation or migration from nonlymphoid tissue.…”

Section: Discussionmentioning

confidence: 99%

IL-7R signaling in regulatory T cells maintains peripheral and allograft tolerance in mice

Schmaler

Broggi

Lagarde

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Foxp3 + CD4 + regulatory T cells (T reg ) have a crucial role in controlling CD4 + T-cell activation, proliferation, and effector function. However, the molecular mechanisms regulating T reg function remain poorly understood. Here we assessed the role of IL-7, a key cytokine regulating T-cell homeostasis, in suppressor capacity of T reg . Using a skin allograft model in which transplant acceptance is controlled by the number of transferred T reg , we find that T reg impair the proliferation of allogeneic CD4 + T cells, decrease production of IFNγ by effector T cells, and prevent early and increase late IL-7 induction by lymph node stromal cells. Increased IL-7 availability enhanced T reg survival, stabilized T reg molecular signature, enhanced surface IL-2Rα expression, and improved IL-2 binding of T reg , which diminished proliferation of alloreactive CD4 + T cells. Sequestration of IL-7 or impairment of IL-7R signaling after allograft transplantation abolished T reg -mediated tolerance by limiting their suppressive capacity. Aged Il7rα-ΔT reg mice displayed mild symptoms of autoimmunity correlating with impaired expansion of effector T reg in response to IL-2. Thus, IL-7R signaling on T reg supports the functional activity of effector T reg by increasing their IL-2 sensitivity in the lymph node during peripheral and allograft tolerance. R egulatory T cells (T reg ) express the transcription factor Foxp3and maintain peripheral tolerance through the suppression of potentially self-reactive T cells (1, 2). T reg deficiency and mutations in FoxP3 result in the development of autoimmune diseases in both humans and mice. The molecular mechanisms underlying the function and stability of the T reg compartment have not been fully elucidated (2-5). T reg constitutively express IL-2Rα (6), in which IL-2 has been shown to regulate T reg survival, expansion, and suppressive function under both homeostatic and activation conditions (7,8). T reg impaired in IL-2Rα signaling fail to suppress effector T-cell responses (7). Because T reg themselves are unable to produce their own IL-2, due to FoxP3-dependent repression of the interleukin-2 (IL-2) gene (9), T reg are susceptible to IL-2 concentrations and need to compete for it in secondary lymphoid organs (SLO) (10). Therefore, competition for IL-2 with conventional T cells is one of the proposed suppressive mechanism of T reg (6).Recently, it was shown that central T reg (cT reg ), defined by CD44 low and CD62L high expression, completely depend on IL-2 during homeostatic and inflammatory conditions, whereas effector T reg (eT reg ), defined by CD44 high and CD62L low expression, require inducible T-cell costimulator (ICOS) signaling (11). Because T reg not only use IL-2 for expansion and proliferation, but also for survival and pool maintenance, it is unclear if IL-2 competition occurs at low IL-2 concentration (as suggested in ref. 12). Moreover, IL-2 signaling via STAT5 (13) stabilizes FOXP3 expression and increases expression of suppressive T reg molecules including ICOS, ...

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The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells

Cited by 537 publications

References 62 publications

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

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

Foxp3+ T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation

IL-7R signaling in regulatory T cells maintains peripheral and allograft tolerance in mice

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The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells

Cited by 537 publications

References 62 publications

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

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

Foxp3+ T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation

IL-7R signaling in regulatory T cells maintains peripheral and allograft tolerance in mice

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

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