National Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
National Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
Cell Rep. 2023 Jan 31;42(1):111991. doi: 10.1016/j.celrep.2023.111991. Epub 2023 Jan 18.
CCR7-triggered DC migration toward draining lymph nodes is critical for the initiation of protective immunity and maintenance of immune tolerance. How to promote CCR7-mediated DC migration to determine T cell responses under inflammatory and homeostatic conditions remains poorly understood. Here we demonstrate that the Extl1 (Exostosin like glycosyltransferase 1) promotes CCR7-triggered DC migration in a heparan sulfate proteoglycans (HSPG)-dependent manner. Mechanistically, Extl1 mediates HSPG production via its glycosyltransferase domain to inhibit C1q expression. Extl1/HSPG axis relieves C1q-mediated restriction of CCR7 surface expression and internalization, and thus enhances CCR7-dependent migratory signaling activation. Consequently, Extl1 is required for DC-mediated Th1 and Th17 responses in immune defense against bacterial infection and for Treg cell development in the prevention of autoimmunity. Our study adds mechanistic insights to the regulation of CCR7-triggered DC migration in immunity and tolerance and provides a potential target for the treatment of infectious and autoimmune diseases.
CCR7 触发的树突状细胞（DC）向引流淋巴结的迁移对于启动保护性免疫和维持免疫耐受至关重要。然而，如何在炎症和稳态条件下促进 CCR7 介导的 DC 迁移以决定 T 细胞反应仍知之甚少。本研究发现，Extl1（Exostosin 样糖基转移酶 1）通过依赖于硫酸乙酰肝素蛋白聚糖（HSPG）的方式促进 CCR7 触发的 DC 迁移。在机制上，Extl1 通过其糖基转移酶结构域介导 HSPG 的产生，从而抑制 C1q 的表达。Extl1/HSPG 轴解除了 C1q 对 CCR7 表面表达和内化的限制，从而增强了 CCR7 依赖性迁移信号的激活。因此，Extl1 对于 DC 介导的对抗细菌感染的 Th1 和 Th17 反应以及预防自身免疫的 Treg 细胞发育是必需的。本研究为 CCR7 触发的 DC 迁移在免疫和耐受中的调控提供了机制上的见解，并为治疗感染和自身免疫性疾病提供了一个潜在的靶点。
