Howard Hughes Medical Institute and Immunology Program at Sloan Kettering Institute, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY.
Immunology and Microbial Pathogenesis Graduate Program, Weill-Cornell Graduate School for Medical Sciences, New York, NY.
J Exp Med. 2021 Apr 5;218(4). doi: 10.1084/jem.20201311.
T cells increase cholesterol biosynthesis upon activation to generate substrates for cellular growth and proliferation. The ubiquitously expressed liver X receptor β (LXRβ) encoded by the Nr1h2 gene is a critical regulator of cholesterol homeostasis in mammalian cells; however, its cell-intrinsic role in T cell biology remains poorly understood. We report that ablation of LXRβ in T cells leads to spontaneous T cell activation and T lymphocytopenia. Unexpectedly, analysis of mixed bone marrow chimeric mice revealed a cell-autonomous survival defect that reduced the fitness of LXRβ-deficient effector T cells, suggesting that the heightened immune activation in mice harboring LXRβ-deficient T cells was due to impaired regulatory T (T reg) cell functionality. Indeed, we found that single-copy deletion of Nr1h2 in T reg cells disrupted activated T reg cell metabolism and fitness and resulted in early-onset fatal autoimmune disease. Our study demonstrated an indispensable requirement for T reg cell-intrinsic LXRβ function in immune homeostasis and provides a basis for immunological therapies through targeting of this receptor.
T 细胞在激活后会增加胆固醇生物合成，为细胞生长和增殖生成底物。由 Nr1h2 基因编码的普遍表达的肝 X 受体 β（LXRβ）是哺乳动物细胞中胆固醇稳态的关键调节剂；然而，其在 T 细胞生物学中的细胞内固有作用仍知之甚少。我们报告称，T 细胞中 LXRβ 的缺失会导致自发的 T 细胞激活和 T 淋巴细胞减少症。出乎意料的是，混合骨髓嵌合小鼠的分析显示出细胞自主生存缺陷，降低了 LXRβ 缺陷效应 T 细胞的适应性，这表明携带 LXRβ 缺陷 T 细胞的小鼠中增强的免疫激活是由于调节性 T（Treg）细胞功能受损所致。事实上，我们发现 Treg 细胞中 Nr1h2 的单拷贝缺失会破坏激活的 Treg 细胞代谢和适应性，并导致早发性致命自身免疫性疾病。我们的研究证明了 Treg 细胞内固有 LXRβ 功能在免疫稳态中的不可或缺的要求，并为通过靶向该受体的免疫治疗提供了基础。
