The transcription factor Bhlhe40 is a switch of inflammatory versus anti-inflammatory Th1 cell fate determination. Mus musculus

Type 1 T helper (Th1) cells play a critical role in host defense against intracellular pathogens and in autoimmune diseases by producing a key inflammatory cytokine interferon (IFN)-γ; some Th1 cells can also be anti-inflammatory through producing IL-10. However, the molecular switch for regulating the differentiation of inflammatory and anti-inflammatory Th1 cells is still elusive. Here we show that Bhlhe40-deficient CD4 Th1 cells produced less IFN-γ but substantially more IL-10 than wild type Th1 cells. Bhlhe40-mediated IFN-γ production was independent of transcription factor T-bet regulation. Mice with conditional deletion of Bhlhe40 in T cells succumbed to Toxoplasma gondii infection and blockage of IL-10 signaling during infection rescued these mice from death. Thus, our results demonstrate that transcription factor Bhlhe40 is a molecular switch for determining the fate of inflammatory and anti-inflammatory Th1 cells. Overall design: RNA-Seq analysis of gene expression in WT stimulated TH1 cells and in Bhlhe40 conditional KO stimulated TH1 mice.

1型辅助性T细胞（Type 1 T helper, Th1）通过分泌关键促炎细胞因子干扰素γ（interferon, IFN-γ），在宿主抗胞内病原体防御及自身免疫病进程中发挥核心作用；部分Th1细胞还可通过分泌白细胞介素10（IL-10）实现抗炎功能。然而，调控促炎与抗炎型Th1细胞分化的分子开关迄今仍未阐明。本研究发现，Bhlhe40缺陷型CD4+ Th1细胞分泌的IFN-γ水平更低，而IL-10的分泌量显著高于野生型Th1细胞。Bhlhe40介导的IFN-γ产生并不依赖转录因子T-bet的调控。T细胞中条件性敲除Bhlhe40的小鼠在感染刚地弓形虫（Toxoplasma gondii）后会死亡，而在感染期间阻断IL-10信号通路可挽救这些小鼠的生命。综上，本研究结果证实转录因子Bhlhe40是决定促炎与抗炎型Th1细胞命运的分子开关。整体实验设计：对野生型（Wild Type, WT）刺激诱导的Th1细胞，以及T细胞条件性敲除Bhlhe40的小鼠刺激诱导的Th1细胞进行基因表达的RNA测序（RNA-Seq）分析。