Autoreactive T cells and cytokine stress drives β-cell senescence entry and accumulation in type 1 diabetes

Type 1 diabetes (T1D) results from a complex dialogue between the immune system and islets characterized by T cell-mediated autoimmune destruction of pancreatic β-cells. In this dialogue, β-cell stress responses have emerged as drug targets for slowing T1D progression, including a subpopulation of senescent β-cells that accumulate during T1D in nonobese diabetic (NOD) mice and humans. However, the mechanisms that cause β-cells to activate senescence in T1D are not known. Here, we show that β-cell senescence entry and accumulation is driven by damage inflicted by autoreactive CD4⁺ and CD8⁺ T cells in the late presymptomatic stages of T1D. Genetically immune-deficient NOD strains showed reduced frequencies of senescent β-cells and adoptive transfer of diabetogenic splenocytes was sufficient to activate β-cell senescence in immune-deficient mice. Modulation of antigen-specific CD4⁺ T cells using an intermittent paradigm of CD3 antibody in immune-competent wild-type NOD mice led to reduced senescence, but did not affect other responses, concomitant with slowing disease progression. Depletion of CD4⁺ or CD8⁺ T cells phenocopied the effect of CD3 antibody on β-cell senescence. CD3 antibody and senolytic ABT-199 had a complementary effect in reducing senescent β-cell burden, consistent with these agents acting in different pathways. Mechanistically, exposure to T1D-related inflammatory cytokines recapitulated stable phenotypes of senescence in human islets and β-cells. Our results demonstrate that β-cell senescence is a stress response that depends on progressive autoreactive CD4⁺ and CD8⁺ T cell damage in T1D and suggests a novel mechanism of action for CD3 immunotherapy in limiting the accumulation of senescent β-cells.