Regulatory T cells (Tregs) subdue immune responses. Central to Treg activation are changes in lipid metabolism that support their survival and function. Fatty acid binding proteins (FABPs) are a family of lipid chaperones required to facilitate uptake and intracellular lipid trafficking. One family member, FABP5, is expressed in T cells, but its function remains unclear. We show that in Tregs, genetic or pharmacologic inhibition of FABP5 function causes mitochondrial changes underscored by decreased OXPHOS, impaired lipid metabolism, and loss of cristae structure. FABP5 inhibition in Tregs triggers mtDNA release and consequent cGAS-STING-dependent type I IFN signaling, which induces heightened production of the regulatory cytokine IL-10 and promotes Treg suppressive activity. We find evidence of this pathway, along with correlative mitochondrial changes in tumor infiltrating Tregs, which may underlie enhanced immunosuppression in the tumor microenvironment. Together, our data reveal that FABP5 is a gatekeeper of mitochondrial integrity that modulates Treg function.

中文翻译：

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脂质代谢调控的线粒体完整性是 Treg 抑制功能的细胞内在检查点。

调节性 T 细胞 (Tregs) 抑制免疫反应。Treg 激活的核心是支持其生存和功能的脂质代谢变化。脂肪酸结合蛋白 (FABP) 是促进摄取和细胞内脂质运输所需的脂质伴侣家族。一个家族成员 FABP5 在 T 细胞中表达，但其功能尚不清楚。我们表明，在 Tregs 中，FABP5 功能的遗传或药理学抑制会导致线粒体变化，而 OXPHOS 减少、脂质代谢受损和嵴结构丧失强调了这一点。Tregs 中的 FABP5 抑制触发 mtDNA 释放和随之而来的 cGAS-STING 依赖性 I 型 IFN 信号传导，从而诱导调节性细胞因子 IL-10 的产生增加并促进 Treg 抑制活性。我们找到了这条途径的证据，以及肿瘤浸润性 Treg 的相关线粒体变化，这可能是肿瘤微环境中增强的免疫抑制的基础。总之，我们的数据表明 FABP5 是调节 Treg 功能的线粒体完整性的看门人。