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

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 ICOSL(+) B 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 ICOSL(+) B 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-ICOSL(+) B cells axis in bridging innate and adaptive immunity and provide potential diagnostic and therapeutic targets for T1D.