Coxsackievirus infection induces direct pancreatic cell killing but poor antiviral CD8⁺ T cell responses

Coxsackievirus B (CVB) infection of pancreatic beta cells is associated with beta cell autoimmunity and type 1 diabetes. We investigated how CVB affects human beta cells and anti-CVB T cell responses. beta cells were efficiently infected by CVB in vitro, down-regulated human leukocyte antigen (HLA) class I, and presented few, selected HLA-bound viral peptides. Circulating CD8(+) T cells from CVB-seropositive individuals recognized a fraction of these peptides; only another subfraction was targeted by effector/memory T cells that expressed exhaustion marker PD-1. T cells recognizing a CVB epitope cross-reacted with beta cell antigen GAD. Infected beta cells, which formed filopodia to propagate infection, were more efficiently killed by CVB than by CVB-reactive T cells. Our in vitro and ex vivo data highlight limited CD8(+) T cell responses to CVB, supporting the rationale for CVB vaccination trials for type 1 diabetes prevention. CD8(+ )T cells recognizing structural and nonstructural CVB epitopes provide biomarkers to differentially follow response to infection and vaccination.