Regulation of peripheral Th/Treg differentiation and suppression of airway inflammation by Nr4a transcription factors

Takashi Sekiya,Shizuko Kagawa,Katsunori Masaki,Koichi Fukunaga,Akihiko Yoshimura,Satoshi Takaki

doi:10.1016/j.isci.2021.102166

Takashi Sekiya, Shizuko Kagawa + Show 4 more

Open Access

https://doi.org/10.1016/j.isci.2021.102166

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Abstract

SummaryHelper T (Th) and regulatory T (Treg) cell differentiation programs promote the eradication of pathogens, while minimizing adverse immune reactions. Here, we found that Nr4a family of nuclear receptors supports Treg cell induction and represses Th1 and Th2 cell differentiation from naive CD4+ T cells. Nr4a factors are transiently induced in CD4+ T cells immediately after antigen stimulation, thereby mediating epigenetic changes. In differentiating Treg cells, Nr4a factors mainly upregulated the early responsive genes in the Treg cell-specifying gene set, either directly or in cooperation with Ets family transcription factors. In contrast, Nr4a factors repressed AP-1 activity by interrupting a positive feedback loop for Batf factor expression, thus suppressing Th2 cell-associated genes. In an allergic airway inflammation model, Nr4a factors suppressed the pathogenesis, mediating oral tolerance. Lastly, pharmacological activation of an engineered Nr4a molecule prevented allergic airway inflammation, indicating that Nr4a factors may be novel therapeutic targets for inflammatory diseases.

Highlights

The CD4+ T cell lineage, comprising immune-activating helper T (Th) cell subsets, including Th1, Th2, Th17, and Tfh, and immune-suppressing regulatory T (Treg) cells, plays pivotal roles in mounting immune responses against diverse types of antigens, while preventing adverse immune responses against self- and commensal-antigens (Zhu et al, 2010)
SUMMARY Helper T (Th) and regulatory T (Treg) cell differentiation programs promote the eradication of pathogens, while minimizing adverse immune reactions
We found that Nr4a family of nuclear receptors supports Treg cell induction and represses Th1 and Th2 cell differentiation from naive CD4+ T cells

Summary

Introduction

The CD4+ T cell lineage, comprising immune-activating helper T (Th) cell subsets, including Th1, Th2, Th17, and Tfh, and immune-suppressing regulatory T (Treg) cells, plays pivotal roles in mounting immune responses against diverse types of antigens, while preventing adverse immune responses against self- and commensal-antigens (Zhu et al, 2010). Th1, Th2, Th17, Tfh, and Treg cell subsets are characterized by their unique expression of transcription factor sets, including T-bet, Gata, Rorgt, Bcl-6, and Foxp, respectively. Fate decisions for the different Th and Treg subsets are largely dependent on the cytokine milieu surrounding the naive T cells (Zhu et al, 2010). In Treg cell differentiation, TGF-b and IL-2 stimulation are indispensable as they activate the transcription factors Smads and Stat, respectively (Chen et al, 2003; Takimoto et al, 2010; Zorn et al, 2006). In contrast to cytokine signaling, T cell receptor (TCR) signaling is commonly required for the differentiation of Th and Treg subsets; TCR signaling is less well characterized as a skewing factor. It has been reported that weak avidity of TCR stimulation favors Th2 cell differentiation (Constant et al, 1995; Hosken et al, 1995)

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