Innate immune-cell-derived BAFF promotes inflammatory response of ICOSL⁺ B cells via non-canonical NF-κB in diabetic autoimmunity.

Abstract

Type 1 diabetes (T1D) is an autoimmune disease resulting from the failure of the immune system to maintain self-tolerance, leading to autoimmune destruction of pancreatic β cells. Although T1D has traditionally been considered as a T cell-driven disease, recent studies have found that B cells play an indispensable role in the pathogenesis. Here, we identified a subset of B cells expressing the inducible T cell co-stimulator ligand (ICOSL), which is associated with T1D progression in cohorts of diabetes patients and mouse models of T1D. Functional analyses revealed that ICOSLB cells contribute to T1D through their enhanced capacity for co-stimulation, proliferation, and inflammatory cytokine production. Furthermore, we demonstrated that innate immune cells promote the generation of pathogenic ICOSLB cell via a B cell activating factor (BAFF)-non-canonical NF-κB signaling axis. Notably, genetic deletion or antibody-mediated blockade of ICOSL inhibited the pro-inflammatory responses of B and T cells and ameliorated autoimmune progression in two mouse models of T1D. Our findings elucidate a novel role of the innate immune cells-BAFF-ICOSLB cells axis in bridging innate and adaptive immunity and provide potential diagnostic and therapeutic targets for T1D.