STAT5 Protein Negatively Regulates T Follicular Helper (Tfh) Cell Generation and Function

Nurieva, Roza; Podd, Andrew; Chen, Yuhong; Alekseev, Andrei; Yu, Mei; Qi, Xiaopeng; Huang, Hua; Wen, Renren; Wang, Junmei; Li, Haiyan S.; Watowich, Stephanie S.; Qi, Hai; Dong, Chen; Wang, Demin

doi:10.1074/jbc.m111.324046

Cited by 201 publications

(224 citation statements)

References 22 publications

(25 reference statements)

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“…It has also recently been reported that STAT5 negatively regulates TfH cell generation (25). In addition, BCL6 expression is low in these cells when STAT5 is activated (25). The authors suggest that STAT5 promotes upregulation of Blimp-1, which then represses BCL6 expression, though they do not directly show that STAT5 regulates Blimp-1 expression.…”

Section: Discussionmentioning

confidence: 91%

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STAT5 Outcompetes STAT3 To Regulate the Expression of the Oncogenic Transcriptional Modulator BCL6

Walker

Nelson

Yeh

et al. 2013

Molecular and Cellular Biology

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Inappropriate activation of the transcription factors STAT3 and STAT5 has been shown to drive cancer pathogenesis through dysregulation of genes involved in cell survival, growth, and differentiation. Although STAT3 and STAT5 are structurally related, they can have opposite effects on key genes, including BCL6. BCL6, a transcriptional repressor, has been shown to be oncogenic in diffuse large B cell lymphoma. BCL6 also plays an important role in breast cancer pathogenesis, a disease in which STAT3 and STAT5 can be activated individually or concomitantly. To determine the mechanism by which these oncogenic transcription factors regulate BCL6 transcription, we analyzed their effects at the levels of chromatin and gene expression. We found that STAT3 increases expression of BCL6 and enhances recruitment of RNA polymerase II phosphorylated at a site associated with transcriptional initiation. STAT5, in contrast, represses BCL6 expression below basal levels and decreases the association of RNA polymerase II at the gene. Furthermore, the repression mediated by STAT5 is dominant over STAT3-mediated induction. STAT5 exerts this effect by displacing STAT3 from one of the two regulatory regions to which it binds. These findings may underlie the divergent biology of breast cancers containing activated STAT3 alone or in conjunction with activated STAT5.

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Section: Discussionmentioning

confidence: 91%

“…BCL6 has been shown to be upregulated by IL-6 and IL-21 to promote differentiation along the TfH lineage (24). It has also recently been reported that STAT5 negatively regulates TfH cell generation (25). In addition, BCL6 expression is low in these cells when STAT5 is activated (25).…”

Section: Discussionmentioning

confidence: 99%

STAT5 Outcompetes STAT3 To Regulate the Expression of the Oncogenic Transcriptional Modulator BCL6

Walker

Nelson

Yeh

et al. 2013

Molecular and Cellular Biology

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“…There has been some evidence of competition between Bcl6 and STATs at cis-regulatory elements, including the Prdm1 gene locus (29,30). Prdm1 expression is driven by STAT5 in CD4 T cells (9,31). To determine if Bcl6 acetylation affects STAT competition, STAT3 and STAT5 ChIP assays were performed at Prdm1 BRE.…”

Section: Significancementioning

confidence: 99%

Bcl6 middle domain repressor function is required for T follicular helper cell differentiation and utilizes the corepressor MTA3

Nance

Bélanger

Johnston

et al. 2015

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

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T follicular helper (Tfh) cells are essential providers of help to B cells. The transcription factor B-cell CLL/lymphoma 6 (Bcl6) is a lineage-defining regulator of Tfh cells and germinal center B cells. In B cells, Bcl6 has the potential to recruit distinct transcriptional corepressors through its BTB domain or its poorly characterized middle domain (also known as RDII), but in Tfh cells the roles of the Bcl6 middle domain have yet to be clarified. Mimicked acetylation of the Bcl6 middle domain (K379Q) in CD4 T cells results in significant reductions in Tfh differentiation in vivo. Blimp1 (Prdm1) is a potent inhibitor of Tfh cell differentiation. Although Bcl6 K379Q still bound to the Prdm1 cis-regulatory elements in Tfh cells, Prdm1 expression was derepressed. This was a result of the failure of Bcl6 K379Q to recruit metastasis-associated protein 3 (MTA3). The loss of Bcl6 function in Bcl6 K379Q-expressing CD4 T cells could be partially rescued by abrogating Prdm1 expression. In addition to Prdm1, we found that Bcl6 recruits MTA3 to multiple genes involved in Tfh cell biology, including genes important for cell migration, cell survival, and alternative differentiation pathways. Thus, Bcl6 middle domain mediated repression is a major mechanism of action by which Bcl6 controls CD4 T-cell fate and function.

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“…Although IL-2 signaling reinforces both Th1 and Th2 effector cell development (22), signaling through IL-2R-associated STAT5 induces Blimp-1 that suppresses Bcl6 expression and Tfh cell commitment (23,24). Collectively, these studies have revealed a mutually antagonistic relationship between codeveloping Tfh and Th1 cells, but although the intracellular signaling and transcriptional events involved have been elucidated, it is currently not clear how extracellular cues establish and maintain this reciprocal regulation.…”

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confidence: 99%

T Follicular Helper, but Not Th1, Cell Differentiation in the Absence of Conventional Dendritic Cells

Dahlgren

Gustafsson-Hedberg

Livingston

et al. 2015

The Journal of Immunology

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Development of long-lived humoral immunity is dependent on CXCR5-expressing T follicular helper (Tfh) cells, which develop concomitantly to effector Th cells that support cellular immunity. Conventional dendritic cells (cDCs) are critical APCs for initial priming of naive CD4+ T cells but, importantly, also provide accessory signals that govern effector Th cell commitment. To define the accessory role of cDCs during the concurrent development of Tfh and effector Th1 cells, we performed high-dose Ag immunization in conjunction with the Th1-biased adjuvant polyinosinic:polycytidylic acid (pI:C). In the absence of cDCs, pI:C failed to induce Th1 cell commitment and IgG2c production. However, cDC depletion did not impair Tfh cell differentiation or germinal center formation, and long-lived IgG1 responses of unaltered affinity developed in mice lacking cDCs at the time point for immunization. Thus, cDCs are required for the pI:C-driven Th1 cell fate commitment but have no crucial accessory function in relation to Tfh cell differentiation.

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STAT5 Protein Negatively Regulates T Follicular Helper (Tfh) Cell Generation and Function

Abstract: Background: Tfh cells regulate B cell-mediated humoral immunity. Results: STAT5 regulated Blimp-1 expression, and STAT5 deficiency in CD4 ϩ T cells resulted in an increase of Tfh generation

Cited by 201 publications

References 22 publications

STAT5 Outcompetes STAT3 To Regulate the Expression of the Oncogenic Transcriptional Modulator BCL6

STAT5 Outcompetes STAT3 To Regulate the Expression of the Oncogenic Transcriptional Modulator BCL6

Bcl6 middle domain repressor function is required for T follicular helper cell differentiation and utilizes the corepressor MTA3

T Follicular Helper, but Not Th1, Cell Differentiation in the Absence of Conventional Dendritic Cells

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