Islet‐Resident Memory T Cells Orchestrate the Immunopathogenesis of Type 1 Diabetes through the FABP4‐CXCL10 Axis

Abstract

Type 1 diabetes (T1D) is a chronic disease characterized by self-destruction of insulin-producing pancreatic β cells by cytotoxic T cell activity. However, the pathogenic mechanism of T cell infiltration remains obscure. Recently, tissue-resident memory T (T_RM) cells have been shown to contribute to cytotoxic T cell recruitment. T_RM cells are found present in human pancreas and are suggested to modulate immune homeostasis. Here, the role of T_RM cells in the development of T1D is investigated. The presence of T_RM cells in pancreatic islets is observed in non-obese diabetic (NOD) mice before T1D onset. Mechanistically, elevated fatty acid-binding protein 4 (FABP4) potentiates the survival and alarming function of T_RM cells by promoting fatty acid utilization and C-X-C motif chemokine 10 (CXCL10) secretion, respectively. In NOD mice, genetic deletion of FABP4 or depletion of T_RM cells using CD69 neutralizing antibodies resulted in a similar reduction of pancreatic cytotoxic T cell recruitment, a delay in diabetic incidence, and a suppression of CXCL10 production. Thus, targeting FABP4 may represent a promising therapeutic strategy for T1D.