CXCL16-dependent scavenging of oxidized LDL acts as a tissue-specific modifier of the exhaustion-like CD8 T cell differentiation program in diabetic autoimmunity.

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B769
Abstract ID: 7656

Presenting Author:
Neetu Srivastava , Staff Scientist at Siteman Cancer Ctr., Barnes-Jewish Hosp. and Washington Univ. Sch. of Med., St. Louis, Washington Univ. Sch. of Med., St. Louis

Abstract:

Autoimmune disorders are characterized by destruction of specific tissues through invasive, antigen-specific responses. Yet, the influence of intrinsic tissue properties on susceptibility to autoimmunity remains uncertain. This study explored whether the proinflammatory features of resident macrophages in pancreatic islets could create an environment conducive to diabetic autoimmunity. Our analysis revealed elevated expression of CXCL16, a chemokine and scavenger receptor for oxidized low-density lipoproteins (OxLDL), in islet macrophages from both mice and humans, irrespective of autoimmune predisposition. Deleting Cxcl16 in NOD mice significantly suppressed the development of T1D. Mechanistically, the loss of Cxcl16 significantly impaired the capacity of islet macrophages to take up OxLDL. This coincided with OxLDL accumulation in pancreatic islets, leading to a reduction in intra-islet transitory (Tex^int) CD8 T cells displaying proliferation and effector signatures. Ferroptosis contributed to the reduction of these intra-islet Tex^int CD8 T cells, which are susceptible to oxidative stress. PD-1 blockade, however, rescued this cell population in the islets and reversed diabetes resistance in Cxcl16-deficient mice. Therefore, OxLDL scavenging by islet macrophages contributes to the local differentiation of pathogenic CD8 T cells. These findings suggest that the normal tissue microenvironment can facilitate autoimmune pathogenesis in predisposed individuals.