BHLHE40 drives protective polyfunctional CD4 T cell differentiation in the female reproductive tract against Chlamydia.
BHLHE40 drives protective polyfunctional CD4 T cell differentiation in the female reproductive tract against Chlamydia.
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BHLHE40 驱动女性生殖道中针对衣原体的保护性多功能 CD4 T 细胞分化。
DOI：
10.1101/2023.11.02.565369
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Li,Lin-Xi
中科院分区：
文献类型：
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作者：
Mercado,MiguelAB;Li,Qiang;Quick,CharlesM;Kim,Yejin;Palmer,Rachel;Huang,Lu;Li,Lin-Xi
蛋白质碱性螺旋-环-螺旋家族成员e40（BHLHE 40）是最近出现的作为宿主对感染、自身免疫性疾病和癌症的免疫的关键调节剂的转录因子。在本研究中，我们研究了Bhlhe 40在女性生殖道（FRT）细胞内衣原体保护性T细胞应答中的作用。Bhlhe 40缺陷小鼠在控制衣原体从FRT脱落的能力方面表现出严重缺陷。Bhlhe 40-/-小鼠中增加的细菌负荷与产生IL-10的调节性T 1型（Tr 1）细胞的显著增加和共同产生IFN-γ、IL-17 A和GM-CSF的多功能CD 4 T细胞的减少相关。IL-10的基因切除或IL-10 R的功能阻断增加了CD 4 T细胞的多功能性，并部分挽救了Bhlhe 40-/-小鼠中细菌控制的缺陷。使用单细胞RNA测序结合TCR分析，我们检测到Bhlhe 40缺陷型CD 4 T细胞中干细胞样T细胞特征的显著富集，而WT CD 4 T细胞在分化轨迹上进一步下降，具有Th 1细胞产生IFN-γ以外的独特效应子功能。总之，我们确定Bhlhe 40作为CD 4 T细胞分化的关键分子驱动因子和FRT中对衣原体的多功能反应。
The protein basic helix-loop-helix family member e40 (BHLHE40) is a transcription factor recently emerged as a key regulator of host immunity to infections, autoimmune diseases and cancer. In this study, we investigated the role ofBhlhe40in protective T cell responses to the intracellular bacteriumChlamydiain the female reproductive tract (FRT). Mice deficient inBhlhe40exhibited severe defects in their ability to controlChlamydia muridarumshedding from the FRT. The heightened bacterial burdens inBhlhe40-/-mice correlated with a marked increase in IL-10-producing T regulatory type 1 (Tr1) cells and decreased polyfunctional CD4 T cells co-producing IFN-γ, IL-17A and GM-CSF. Genetic ablation of IL-10 or functional blockade of IL-10R increased CD4 T cell polyfunctionality and partially rescued the defects in bacterial control inBhlhe40-/-mice. Using single-cell RNA sequencing coupled with TCR profiling, we detected a significant enrichment of stem-like T cell signatures inBhlhe40-deficient CD4 T cells, whereas WT CD4 T cells were further down on the differentiation trajectory with distinct effector functions beyond IFN-γ production by Th1 cells. Altogether, we identifiedBhlhe40as a key molecular driver of CD4 T cell differentiation and polyfunctional responses in the FRT againstChlamydia.