Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, 95817, USA.
Nat Commun. 2020 Jun 5;11(1):2859. doi: 10.1038/s41467-020-16636-4.
Mature double negative (DN) T cells are a population of αβ T cells that lack CD4 and CD8 coreceptors and contribute to systemic lupus erythematosus (SLE). The splenic marginal zone macrophages (MZMs) are important for establishing immune tolerance, and loss of their number or function contributes to the progression of SLE. Here we show that loss of MZMs impairs the tolerogenic clearance of apoptotic cells and alters the serum cytokine profile, which in turn provokes the generation of DN T cells from self-reactive CD8 T cells. Increased Ki67 expression, narrowed TCR V-beta repertoire usage and diluted T-cell receptor excision circles confirm that DN T cells from lupus-prone mice and patients with SLE undergo clonal proliferation and expansion in a self-antigen dependent manner, which supports the shared mechanisms for their generation. Collectively, our results provide a link between the loss of MZMs and the expansion of DN T cells, and indicate possible strategies to prevent the development of SLE.
成熟的双阴性 (DN) T 细胞是一群缺乏 CD4 和 CD8 核心受体的 αβ T 细胞，它们与系统性红斑狼疮 (SLE) 的发生有关。脾脏边缘区巨噬细胞 (MZMs) 对于建立免疫耐受很重要，其数量或功能的丧失会导致 SLE 的进展。在这里，我们发现 MZMs 的缺失会损害凋亡细胞的耐受性清除，并改变血清细胞因子谱，进而促使自身反应性 CD8 T 细胞产生 DN T 细胞。Ki67 表达增加、TCR V-beta repertoire 使用范围变窄以及 T 细胞受体切除环稀释均证实，来自狼疮易感小鼠和 SLE 患者的 DN T 细胞以自身抗原依赖的方式发生克隆性增殖和扩增，这支持了它们产生的共同机制。总的来说，我们的研究结果在 MZMs 的缺失与 DN T 细胞的扩增之间建立了联系，并为预防 SLE 的发生提供了可能的策略。
