An IL-4-independent and CD25-mediated function of c-maf in promoting the production of Th2 cytokines

Hwang, Eun Sook; White, Ian Alexander; Ho, I‐Cheng

doi:10.1073/pnas.202474499

Cited by 54 publications

(51 citation statements)

References 23 publications

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“…Given the importance of STAT5 in IL-4 transcription and the fact that CD25 high cells are those cells with higher pSTAT5 levels, it is thus not surprisingly that the early IL-4 producers are exclusively CD25 high cells. This result is in part consistent with previous findings that the level of CD25 expression is significantly higher in developing Th2 cells than in developing Th1 cells during in vitro T cell differentiation (51). Interestingly, CD4 T cells activated by TLR-stimulated DCs proliferate at least as effectively as those activated by DCs pulsed with Ag alone (15), supporting the view that IL-2 signaling through STAT5 phosphorylation is not crucial for CD4 T cell proliferation (27) (data not shown).…”

Section: Discussionsupporting

confidence: 93%

Suppression of Early IL-4 Production Underlies the Failure of CD4 T Cells Activated by TLR-Stimulated Dendritic Cells to Differentiate into Th2 Cells

Sun

Pearce

2007

The Journal of Immunology

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Dendritic cells (DCs) activated through TLRs provide a potent negative signal for Th2 cell development that is independent of positive signals for Th1 cell development such as IL-12 and IFN-γ. In this study we demonstrate that the ability of TLR-activated DCs to suppress Th2 cell development is Ag dose-independent and unique to DCs that have been activated through TLRs vs by cytokines. We show that TLR-activated DCs inhibit early IL-4 production by CD4 T cells and thus inhibit their ability to subsequently increase GATA-3 expression and commit to the Th2 lineage. This occurs independently of expression of the GATA-3 antagonist T-bet. Although CD4 T cells activated by TLR-activated DCs make IL-2, they are not capable of phosphorylating STAT5 in response to this cytokine. This inhibition of responsiveness to IL-2 appears to underlie the failure to make early IL-4. Our findings suggest that DCs provide instructional signals for T cell differentiation before cytokine-mediated Th cell selection and outgrowth.

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Section: Discussionsupporting

confidence: 93%

Suppression of Early IL-4 Production Underlies the Failure of CD4 T Cells Activated by TLR-Stimulated Dendritic Cells to Differentiate into Th2 Cells

Sun

Pearce

2007

The Journal of Immunology

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“…Therefore, it is unlikely that IL-4 is an upstream cytokine for Stat5a-mediated Th2 cell differentiation. In contrast, it has recently been shown that developing Th2 cells express higher levels of IL-2R ␣-chain and exhibit stronger Stat5 activation than developing Th1 cells (35). This is consistent with a previous finding that Stat5a functions as an enhancer of IL-2 signaling by inducing the expression of IL-2R ␣-chain (23).…”

Section: Stat6supporting

confidence: 92%

“…This is consistent with a previous finding that Stat5a functions as an enhancer of IL-2 signaling by inducing the expression of IL-2R ␣-chain (23). Moreover, it has been demonstrated that Th2 cell differentiation is decreased by the neutralization of IL-2 or the blocking of IL-2R (18,35,36). Furthermore, it has been demonstrated that IL-2, but not IL-4, IL-9, IL-15, or IL-21, induces Stat5 phosphorylation and IL-4 production in activated CD4 ϩ T cells (37).…”

Section: Stat6mentioning

confidence: 99%

Indispensable Role of Stat5a in Stat6-Independent Th2 Cell Differentiation and Allergic Airway Inflammation

Takatori

Nakajima

Hirose

et al. 2005

The Journal of Immunology

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It is well-recognized that Stat6 plays a critical role in Th2 cell differentiation and the induction of allergic inflammation. We have previously shown that Stat5a is also required for Th2 cell differentiation and allergic airway inflammation. However, it is the relative importance and redundancy of Stat6 and Stat5a in Th2 cell differentiation and allergic airway inflammation are unknown. In this study we addressed these issues by comparing Stat5a-deficient (Stat5a−/−) mice, Stat6−/− mice, and Stat5a- and Stat6 double-deficient (Stat5a−/− Stat6−/−) mice on the same genetic background. Th2 cell differentiation was severely decreased in Stat6−/−CD4+ T cells, but Stat6-independent Th2 cell differentiation was still significantly observed in Stat6−/−CD4+ T cells. However, even in the Th2-polarizing condition (IL-4 plus anti-IFN-γ mAb), no Th2 cells developed in Stat5a−/−Stat6−/− CD4+ T cells. Moreover, Ag-induced eosinophil and lymphocyte recruitment in the airways was severely decreased in Stat5a−/−Stat6−/− mice compared with that in Stat6−/− mice. These results indicate that Stat5a plays an indispensable role in Stat6-independent Th2 cell differentiation and subsequent Th2 cell-mediated allergic airway inflammation.

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“…The existence of additional targets is suggested by studies demonstrating that IL-4-independent changes occur in CD4 cells from c-Maf-transgenic (Tg) mice [7,19]. Here, we present data that expand the function of c-Maf beyond simple transactivation of the IL-4 gene to include regulation of Bcl-2 expression in CD4 cells.…”

mentioning

confidence: 72%

c‐Maf interacts with c‐Myb to down‐regulate Bcl‐2 expression and increase apoptosis in peripheral CD4 cells

et al. 2007

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The transcription factor c‐Maf is critical for IL‐4 production and the development of Th2 cells, which promote humoral immunity and protect against extracellular parasites. Yet, little else is known of c‐Maf function in CD4 cells. Here, we identify a novel role for c‐Maf in regulating susceptibility to apoptosis. Overexpression of c‐Maf results in increased susceptibility of CD4 cells to apoptosis induced by multiple stimuli, including growth factor withdrawal, dexamethasone, irradiation, and TCR engagement. This effect is independent of Fas or p53; however, Bcl‐2 expression is reduced in c‐Maf Tg CD4 cells. Immunoprecipitation and Western blot analyses demonstrate that c‐Maf–c‐Myb complex formation is enhanced among T cells from c‐Maf Tg mice compared to non‐Tg littermates following TCR engagement. Unlike non‐Tg T cells, c‐Myb binding to the Bcl‐2 promoter is not detectable in c‐Maf Tg T cells by chromatin immunoprecipitation. In reporter assays, Bcl‐2 promoter activity is reduced by c‐Maf in a dose‐dependent manner. Furthermore, transgene‐mediated Bcl‐2 expression corrects the apoptosis defect observed among c‐Maf Tg CD4 cells. These data suggest that c‐Maf can interact with c‐Myb to reduce Bcl‐2 expression, thereby limiting CD4 cell survival following TCR engagement.

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An IL-4-independent and CD25-mediated function of c-maf in promoting the production of Th2 cytokines

Cited by 54 publications

References 23 publications

Suppression of Early IL-4 Production Underlies the Failure of CD4 T Cells Activated by TLR-Stimulated Dendritic Cells to Differentiate into Th2 Cells

Suppression of Early IL-4 Production Underlies the Failure of CD4 T Cells Activated by TLR-Stimulated Dendritic Cells to Differentiate into Th2 Cells

Indispensable Role of Stat5a in Stat6-Independent Th2 Cell Differentiation and Allergic Airway Inflammation

c‐Maf interacts with c‐Myb to down‐regulate Bcl‐2 expression and increase apoptosis in peripheral CD4 cells

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