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