Coxsackievirus B escapes antiviral CD8+ T cells but triggers robust CD4+ memory responses.

Coxsackieviruses B (CVBs) are plausible triggers of the pancreatic islet autoimmunity leading to type 1 diabetes. Islet autoantibody seroconversion correlates with persistent CVB infections in the gut and pancreas, suggesting defective antiviral control and the need to define immune mechanisms at the intestinal entry site. We investigated how CVB3 modulates antigen presentation, the viral immunopeptidome of enterocytes and antigen-presenting cells, and downstream T cell immunity. CVB3-infected enterocytes evaded immune recognition by down-regulating human leukocyte antigen (HLA) class I and viral peptide presentation, impairing CD8+ T cell responses in vitro. In CVB-seropositive individuals, circulating CVB-reactive CD8+ T cells were stalled in naïve-like and exhausted effector/memory states. In contrast, CVB3 induced HLA class II up-regulation, promoting robust CD4+ T cell activation. Circulating CVB3-reactive CD4+ T cells fully differentiated into polyfunctional T helper memory. These findings indicate that CVB3 antiviral control is predominantly CD4+ T cell mediated and provide a rationale for mucosal vaccination strategies and immune monitoring tools to follow infection or vaccination.