Department of Neuroscience, University of Virginia, Charlottesville, Virginia, United States of America.
Neuroscience Graduate Program, University of Virginia, Charlottesville Virginia, United States of America.
PLoS Biol. 2023 Feb 14;21(2):e3002000. doi: 10.1371/journal.pbio.3002000. eCollection 2023 Feb.
Multiple sclerosis (MS) is a T cell-driven autoimmune disease that attacks the myelin of the central nervous system (CNS) and currently has no cure. MS etiology is linked to both the gut flora and external environmental factors but this connection is not well understood. One immune system regulator responsive to nonpathogenic external stimuli is the aryl hydrocarbon receptor (AHR). The AHR, which binds diverse molecules present in the environment in barrier tissues, is a therapeutic target for MS. However, AHR's precise function in T lymphocytes, the orchestrators of MS, has not been described. Here, we show that in a mouse model of MS, T cell-specific Ahr knockout leads to recovery driven by a decrease in T cell fitness. At the mechanistic level, we demonstrate that the absence of AHR changes the gut microenvironment composition to generate metabolites that impact T cell viability, such as bile salts and short chain fatty acids. Our study demonstrates a newly emerging role for AHR in mediating the interdependence between T lymphocytes and the microbiota, while simultaneously identifying new potential molecular targets for the treatment of MS and other autoimmune diseases.
多发性硬化症（MS）是一种 T 细胞驱动的自身免疫性疾病，攻击中枢神经系统（CNS）的髓鞘，目前尚无治愈方法。MS 的病因与肠道菌群和外部环境因素都有关，但这种联系还不是很清楚。一种对非致病性外部刺激有反应的免疫系统调节剂是芳香烃受体（AHR）。AHR 与屏障组织中存在的各种环境分子结合，是 MS 的治疗靶点。然而，AHR 在 T 淋巴细胞（MS 的协调者）中的精确功能尚未被描述。在这里，我们发现在 MS 的小鼠模型中，T 细胞特异性 Ahr 敲除导致 T 细胞适应性降低驱动的恢复。在机制水平上，我们证明了 AHR 的缺失改变了肠道微生物环境的组成，产生了影响 T 细胞活力的代谢物，如胆汁盐和短链脂肪酸。我们的研究表明，AHR 在介导 T 淋巴细胞和微生物群之间的相互依存关系方面发挥着新的作用，同时也为 MS 和其他自身免疫性疾病的治疗确定了新的潜在分子靶点。
