Basic leucine zipper transcription factor, ATF-like (BATF) regulates epigenetically and energetically effector CD8 T-cell differentiation via Sirt1 expression

Kuroda, Seika; Yamazaki, Maya; Abe, Manabu; Sakimura, Kenji; Takayanagi, Hiroshi; Iwai, Yoshiko

doi:10.1073/pnas.1105133108

Cited by 96 publications

(85 citation statements)

References 30 publications

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“…This raises the question of whether other STAT3 cytokines elevated during the later phases of LCMV Cl13 infection, such as IL-10, IL-27 and IL-6, can also induce BATF expression in CD8 T cells. In addition, other signals, such as IL-12 and PD-1 ligation, can also induce BATF expression in CD8 T cells (Kuroda et al, 2011; Quigley et al, 2010). The relative contribution of these various pathways to the regulation of BATF expression requires further study.…”

Section: Discussionmentioning

confidence: 99%

A Critical Role of IL-21-Induced BATF in Sustaining CD8-T-Cell-Mediated Chronic Viral Control

et al. 2015

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Summary Control of chronic viral infections by CD8 T cells is critically dependent on CD4 help. In particular, helper-derived IL-21 plays a key role in sustaining the CD8 T cell response, however the molecular pathways by which IL-21 sustains CD8 T cell immunity remain unclear. We demonstrate that IL-21 causes a phenotypic switch of transcription factor expression in CD8 T cells during chronic viral infection characterized by sustained BATF expression. Importantly, BATF expression during chronic infection is both required for optimal CD8 T cell persistence and anti-viral effector function, and sufficient to rescue “unhelped” CD8 T cells. Mechanistically, BATF sustains the response by cooperating with IRF4, an antigen-induced transcription factor that is also critically required for CD8 T cell maintenance, to preserve Blimp-1 expression and thereby sustain CD8 T cell effector function. Collectively, these data suggest that CD4 T cells “help” the CD8 response during chronic infection via IL-21-induced BATF expression.

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Section: Discussionmentioning

confidence: 99%

A Critical Role of IL-21-Induced BATF in Sustaining CD8-T-Cell-Mediated Chronic Viral Control

et al. 2015

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“…BATF-deficient mice show impaired effector CD8 + T-cell differentiation, characterized by reduced expression of IFN-γ, Perforin, and T-bet, which was caused by changes in epigenetic remodeling and energy metabolism (32). It is possible that BATF and IRF4 cooperatively affect CD8 + T-cell effector differentiation either by regulation of effector proteins and TFs or by promoting changes in metabolic pathways.…”

Section: Discussionmentioning

confidence: 99%

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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“…Sirt1 has emerged as a critical immune regulator by suppressing T cell immunity and macrophage functions (5,7,16,43,44), providing a rationale for Sirt1 activators in autoimmune and inflammatory disease therapy. Our findings here show that Sirt1 suppresses DC production of IL-27 and IFN-␤, two antiinflammatory cytokines that negatively regulate CD4 ϩ T cell differentiation toward Th17, indicating that Sirt1 may tune or function as a balance keeper for the immune response during inflammation.…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Sirtuin 1 Deacetylates IRF1 Protein and Programs Dendritic Cells to Control Th17 Protein Differentiation during Autoimmune Inflammation

Yang

Lee

Gao

et al. 2013

Journal of Biological Chemistry

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Background:The roles of Sirt1 in regulating dendritic functions are not known. Results: Sirt1 deacetylates the IRF1 transcription factor to suppress IL-27 expression in dendritic cells, leading to elevated Th17 differentiation for inflammatory disease development. Conclusion: Sirt1 programs DC functions to promote Th17 differentiation and inflammation. Significance: This study defines a previously unappreciated inflammatory role of Sirt1 in dendritic cells.

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Basic leucine zipper transcription factor, ATF-like (BATF) regulates epigenetically and energetically effector CD8 T-cell differentiation via Sirt1 expression

Cited by 96 publications

References 30 publications

A Critical Role of IL-21-Induced BATF in Sustaining CD8-T-Cell-Mediated Chronic Viral Control

A Critical Role of IL-21-Induced BATF in Sustaining CD8-T-Cell-Mediated Chronic Viral Control

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

Histone Deacetylase Sirtuin 1 Deacetylates IRF1 Protein and Programs Dendritic Cells to Control Th17 Protein Differentiation during Autoimmune Inflammation

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Basic leucine zipper transcription factor, ATF-like (BATF) regulates epigenetically and energetically effector CD8 T-cell differentiation via Sirt1 expression

Cited by 96 publications

References 30 publications

A Critical Role of IL-21-Induced BATF in Sustaining CD8-T-Cell-Mediated Chronic Viral Control

A Critical Role of IL-21-Induced BATF in Sustaining CD8-T-Cell-Mediated Chronic Viral Control

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

Histone Deacetylase Sirtuin 1 Deacetylates IRF1 Protein and Programs Dendritic Cells to Control Th17 Protein Differentiation during Autoimmune Inflammation

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