Coxsackievirus infection induces direct pancreatic β-cell killing but poor anti-viral CD8+ T-cell responses

Vecchio, F.; Carre, A.; Korenkov, D.; Zhou, Z.; Apaolaza, P.; Tuomela, S.; Burgos-Morales, O.; Snowhite, I.; Perez-Hernandez, J.; Brandao, B.; Afonso, G.; Halliez, C.; Kaddis, J.; Kent, S. C.; Nakayama, M.; Richardson, S. J.; Vinh, J.; Verdier, Y.; Laiho, J.; Scharfmann, R.; Solimena, M.; Marinicova, Z.; Bismuth, E.; Lucidarme, N.; Sanchez, J.; Bustamante, C.; Gomez, P.; Buus, S.; the nPOD-Virus Working Group,; You, S.; Pugliese, A.; Hyoty, H.; Rodriguez-Calvo, T.; Flodstrom-Tullberg, M.; Mallone, R.

doi:10.1101/2023.08.19.553954

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bioRxiv · 10.1101/2023.08.19.553954

Coxsackievirus infection induces direct pancreatic β-cell killing but poor anti-viral CD8+ T-cell responses

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Abstract

Coxsackievirus B (CVB) infection of pancreatic {beta} cells is associated with {beta}-cell autoimmunity. We investigated how CVB impacts human {beta} cells and anti-CVB T-cell responses. {beta} 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 {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. Thus, our in-vitro and ex-vivo data highlight limited T-cell responses to CVB, supporting the rationale for CVB vaccination trials for type 1 diabetes prevention. CD8+ T cells recognizing structural and non-structural CVB epitopes provide biomarkers to differentially follow response to infection and vaccination.

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Vecchio, F., Carre, A., Korenkov, D., Zhou, Z., Apaolaza, P., Tuomela, S., Burgos-Morales, O., Snowhite, I., Perez-Hernandez, J., Brandao, B., Afonso, G., Halliez, C., Kaddis, J., Kent, S. C., Nakayama, M., Richardson, S. J., Vinh, J., Verdier, Y., Laiho, J., Scharfmann, R., Solimena, M., Marinicova, Z., Bismuth, E., Lucidarme, N., Sanchez, J., Bustamante, C., Gomez, P., Buus, S., the nPOD-Virus Working Group,, You, S., Pugliese, A., Hyoty, H., Rodriguez-Calvo, T., Flodstrom-Tullberg, M., Mallone, R.. 2023-08-21. Coxsackievirus infection induces direct pancreatic β-cell killing but poor anti-viral CD8+ T-cell responses. https://doi.org/10.1101/2023.08.19.553954

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