Initiation and maintenance of Th2 cell identity

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Epigenetic modifications, such as posttranslational modifications of histones, play an important role in gene expression and regulation. These modifications are in part mediated by the Trithorax group (TrxG) complex and the Polycomb group (PcG) complex, which activate and repress transcription, respectively. We herein investigate the role of Menin, a component of the TrxG complex in T helper (Th) cell differentiation and show a critical role for Menin in differentiation and maintenance of Th17 cells. Menin −/− T cells do not efficiently differentiate into Th17 cells, leaving Th1 and Th2 cell differentiation intact in in vitro cultures. Menin deficiency resulted in the attenuation of Th17-induced airway inflammation. In differentiating Th17 cells, Menin directly bound to the Il17a gene locus and was required for the deposition of permissive histone modifications and recruitment of the RNA polymerase II transcriptional complex. Interestingly, although Menin bound to the Rorc locus, Menin was dispensable for the induction of Rorc expression and permissive histone modifications in differentiating Th17 cells. In contrast, Menin was required to maintain expression of Rorc in differentiated Th17 cells, indicating that Menin is essential to stabilize expression of the Rorc gene. Thus, Menin orchestrates Th17 cell differentiation and function by regulating both the induction and maintenance of target gene expression.

Section: Discussionsupporting

confidence: 49%

“…It has been reported that the Menin/TrxG complex binds to DNA through RNAPII (22,40). We demonstrate that Menin directly bound to the Il17a gene locus and induced permissive histone modifications in differentiating Th17 cells (Fig.…”

Section: Discussionmentioning

confidence: 78%

Trithorax complex component Menin controls differentiation and maintenance of T helper 17 cells

Watanabe¹,

Onodera²,

Kanai³

et al. 2014

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“…These two functionally distinct complexes exist in the same developing Th2 cells and coordinately establish Th2 cell identity. Although a requirement for Gata3-mediated chromatin remodeling at the Th2 cytokine gene loci during Th2 cell differentiation has been well established (26), the molecular mechanisms underlying Gata3-mediated chromatin remodeling remain unknown. Discovery of the Chd4/Gata3 interaction and the critical role of Chd4 in the initial step of Gata3-mediated chromatin remodeling, including H3-K9 hyperacetylation of the Th2 cytokine gene loci, provides key mechanistic insight into this process (Fig.…”

Section: Discussionmentioning

confidence: 99%

Functionally distinct Gata3/Chd4 complexes coordinately establish T helper 2 (Th2) cell identity

Hosokawa¹,

Tanaka

Suzuki

et al. 2013

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GATA binding protein 3 (Gata3) is a GATA family transcription factor that controls differentiation of naïve CD4 T cells into T helper 2 (Th2) cells. However, it is unknown how Gata3 simultaneously activates Th2-specific genes while repressing those of other Th lineages. Here we show that chromodomain helicase DNA-binding protein 4 (Chd4) forms a complex with Gata3 in Th2 cells that both activates Th2 cytokine transcription and represses the Th1 cytokine IFN-γ. We define a Gata3/Chd4/p300 transcriptional activation complex at the Th2 cytokine loci and a Gata3/Chd4–nucleosome remodeling histone deacetylase repression complex at the Tbx21 locus in Th2 cells. We also demonstrate a physiological role for Chd4 in Th2-dependent inflammation in an in vivo model of asthmatic inflammation. Thus, Gata3/Chd4 forms functionally distinct complexes, which mediate both positive and negative gene regulation to facilitate Th2 cell differentiation.

“…After antigen clearance, most effector Th cells are thought to undergo apoptotic cell death during a period known as the contraction phase (8); however, some effector CD4 T cells escape cell death, differentiate into memory CD4 T cells, and survive for long periods in vivo. Once long-lived memory T cells are established, these cells persist for months and years, accompanied by slow basal turnover and homeostasis (9)(10)(11)(12), while maintaining the ability to proliferate and produce polarized cytokines on antigen reencounter (13). In addition, heterogeneity in cytokine production potential is suggested in memory CD4 T cells (3,(13)(14)(15).…”

mentioning

confidence: 99%

“…Once long-lived memory T cells are established, these cells persist for months and years, accompanied by slow basal turnover and homeostasis (9)(10)(11)(12), while maintaining the ability to proliferate and produce polarized cytokines on antigen reencounter (13). In addition, heterogeneity in cytokine production potential is suggested in memory CD4 T cells (3,(13)(14)(15). However, once memory cells are established, factors that influence memory CD4 + Th-cell pool size and function remain poorly defined.…”

mentioning

confidence: 99%

Regulation of memory CD4 T-cell pool size and function by natural killer T cells in vivo

Iwamura

Shinoda

Endo

et al. 2012

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To develop more effective vaccines and strategies to regulate chronic inflammatory diseases, it is important to understand the mechanisms of immunological memory. Factors regulating memory CD4 + T helper (Th)-cell pool size and function remain unclear, however. We show that activation of type I invariant natural killer T (iNKT) cells with glycolipid ligands and activation of type II natural killer T (NKT) cells with the endogenous ligand sulfatide induced dramatic proliferation and expansion of memory, but not naïve, CD4 T cells. NKT cell-induced proliferation of memory Th1 and Th2 cells was dependent largely on the production of IL-2, with Th2-cell proliferation also affected by loss of IL-4. Type II NKT cells were also required for efficient maintenance of memory CD4 T cells in vivo. Activation of iNKT cells resulted in up-regulation of IFN-γ expression by memory Th2 cells. These IFN-γ-producing memory Th2 cells showed a decreased capability to induce Th2 cytokines and eosinophilic airway inflammation. Thus, activated NKT cells directly regulate memory CD4 T-cell pool size and function via the production of cytokines in vivo.α-galactosylceramide | CD1d KO mice | Jα18 KO mice | STAT5 | allergy