美国华盛顿大学医学院Wan Xiaoxiao研究组在研究中取得进展。他们探明了胰岛巨噬细胞对氧化脂的CXCL16依赖性清除，促进了糖尿病自身免疫中致病性CD8+ T细胞的分化。相关论文于2024年5月15日发表在《免疫》杂志上。

该研究组研究了胰岛常驻巨噬细胞在引发1型糖尿病的自身免疫攻击中的作用。胰岛巨噬细胞高度表达CXCL16，一种氧化低密度脂蛋白(OxLDLs)的趋化因子和清除受体，与自身免疫性易感性无关。在非肥胖型糖尿病(NOD)小鼠中缺失Cxcl16抑制自身免疫性糖尿病的发展。

从机制上说，Cxcl16缺乏会损害胰岛巨噬细胞对OxLDL的清除，导致OxLDL在胰岛积累，并导致胰岛内短暂性(Tex^int) 显示增殖和效应特征的CD8⁺ T细胞大幅减少。Tex^int细胞易受氧化应激，并因铁死亡而减少；PD-1阻断挽救了这一人群，并逆转了NOD .Cxcl16^{−/−小鼠}的糖尿病抵抗。因此，胰岛中的OxLDL清除无意中促进了致病性CD8⁺ T细胞的分化，呈现出一种范式，即组织稳态过程可以促进易感个体的自身免疫发病。

附：英文原文

Title: CXCL16-dependent scavenging of oxidized lipids by islet macrophages promotes differentiation of pathogenic CD8+ T cells in diabetic autoimmunity

Author: Neetu Srivastava, Hao Hu, Orion J. Peterson, Anthony N. Vomund, Marta Stremska, Mohammad Zaman, Shilpi Giri, Tiandao Li, Cheryl F. Lichti, Pavel N. Zakharov, Bo Zhang, Nada A. Abumrad, Yi-Guang Chen, Kodi S. Ravichandran, Emil R. Unanue, Xiaoxiao Wan

Issue&Volume: 2024-05-15

Abstract: The pancreatic islet microenvironment is highly oxidative, rendering β cells vulnerable to autoinflammatory insults. Here, we examined the role of islet resident macrophages in the autoimmune attack that initiates type 1 diabetes. Islet macrophages highly expressed CXCL16, a chemokine and scavenger receptor for oxidized low-density lipoproteins (OxLDLs), regardless of autoimmune predisposition. Deletion of Cxcl16 in nonobese diabetic (NOD) mice suppressed the development of autoimmune diabetes. Mechanistically, Cxcl16 deficiency impaired clearance of OxLDL by islet macrophages, leading to OxLDL accumulation in pancreatic islets and a substantial reduction in intra-islet transitory (Texint) CD8+ T cells displaying proliferative and effector signatures. Texint cells were vulnerable to oxidative stress and diminished by ferroptosis; PD-1 blockade rescued this population and reversed diabetes resistance in NOD.Cxcl16/ mice. Thus, OxLDL scavenging in pancreatic islets inadvertently promotes differentiation of pathogenic CD8+ T cells, presenting a paradigm wherein tissue homeostasis processes can facilitate autoimmune pathogenesis in predisposed individuals.

DOI: 10.1016/j.immuni.2024.04.017

Source: https://www.cell.com/immunity/fulltext/S1074-7613(24)00222-X