Abstract
Coxsackievirus B (CVB) infection of pancreatic β cells is associated with β cell autoimmunity and type 1 diabetes. We investigated how CVB affects human β cells and anti-CVB T cell responses. β 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 β cell antigen GAD. Infected β 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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | eadl1122 |
| Tidsskrift | Science Advances |
| Vol/bind | 10 |
| Udgave nummer | 10 |
| Antal sider | 16 |
| ISSN | 2375-2548 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:We thank the cochin institute cyBio Flow cytometry core Facility for assistance with cell analysis and sorting. We gratefully acknowledge V. hytönen (University of tampere, Finland) for the gift of the anti-VP1 mAb 3A6; l. Whitton (the Scripps Research institute, la Jolla, cA, USA) for the gift of the cVB3-eGFP strain; S. Oikarinen and M. hankaniemi (University of tampere, Finland) for cVB sequencing and dynamic light scattering quality controls; and M. Peakman (King’s college, london) for providing the 1e6 tcR sequence. this work was supported by JdRF nPOd-Virus grant 3-SRA-2017-492-A-n (A.P.); JdRF Postdoctoral Fellowship 3-PdF-2020-942-A-n (Z.Z.); novo nordisk Postdoctoral Fellowship program at Karolinska institutet (S.t.); Steve Morgan Foundation Grand challenge Senior Research Fellowship 22/0006504 (S.J.R.); national institutes of health niddK grant R01dK099317 (M.n.); Federal Ministry for education and Research (BMBF) to the German center for diabetes Research (dZd e.V.) (M.S.); Strategic Research Program in diabetes at Karolinska institutet (M.F.-t.); the Swedish child diabetes Foundation and the Swedish Research council (M.F.-t.); Agence nationale de la Recherche grant AnR-19-ce15-0014-01 (R.M.); Fondation pour la Recherche Medicale grant eQU20193007831 (R.M.); innovative Medicines initiative 2 Joint Undertaking grants 115797 (innOdiA) and 945268 (innOdiA hARVeSt), which receive support from the eU horizon 2020 program, the european Federation of Pharmaceutical industries and Associations, JdRF, and the leona M. & harry B. helmsley charitable trust (S.J.R., R.S., M.S., t.R.-c., and R.M.); support of the human Atlas of neonatal development and early life immunity program (hAndel-i; RRid:ScR_021947) sponsored by the leona M. & harry B. helmsley charitable trust; and support of nPOd (RRid: ScR_014641), a collaborative t1d research project sponsored by JdRF (nPOd: 5-SRA-2018-557-Q-R) and the leona M. & harry B. helmsley charitable trust (2018PG-t1d053). Organ Procurement Organizations partnering with nPOd to provide research resources are listed at
Funding Information:
Acknowledgments: We thank the cochin institute cyBio Flow cytometry core Facility for assistance with cell analysis and sorting. We gratefully acknowledge V. hytönen (University of tampere, Finland) for the gift of the anti-VP1 mAb 3A6; l. Whitton (the Scripps Research institute, la Jolla, cA, USA) for the gift of the cVB3-eGFP strain; S. Oikarinen and M. hankaniemi (University of tampere, Finland) for cVB sequencing and dynamic light scattering quality controls; and M. Peakman (King’s college, london) for providing the 1e6 tcR sequence. Funding: this work was supported by JdRF nPOd-Virus grant 3-SRA-2017-492-A-n (A.P.); JdRF Postdoctoral Fellowship 3-PdF-2020-942-A-n (Z.Z.); novo nordisk Postdoctoral Fellowship program at Karolinska institutet (S.t.); Steve Morgan Foundation Grand challenge Senior Research Fellowship 22/0006504 (S.J.R.); national institutes of health niddK grant R01dK099317 (M.n.); Federal Ministry for education and Research (BMBF) to the German center for diabetes Research (dZd e.V.) (M.S.); Strategic Research Program in diabetes at Karolinska institutet (M.F.-t.); the Swedish child diabetes Foundation and the Swedish Research council (M.F.-t.); Agence nationale de la Recherche grant AnR-19-ce15-0014-01 (R.M.); Fondation pour la Recherche Medicale grant eQU20193007831 (R.M.); innovative Medicines initiative 2 Joint Undertaking grants 115797 (innOdiA) and 945268 (innOdiA hARVeSt), which receive support from the eU horizon 2020 program, the european Federation of Pharmaceutical industries and Associations, JdRF, and the leona M. & harry B. helmsley charitable trust (S.J.R., R.S., M.S., t.R.-c., and R.M.); support of the human Atlas of neonatal development and early life immunity program (hAndel-i; RRid:ScR_021947) sponsored by the leona M. & harry B. helmsley charitable trust; and support of nPOd (RRid: ScR_014641), a collaborative t1d research project sponsored by JdRF (nPOd: 5-SRA-2018-557-Q-R) and the leona M. & harry B. helmsley charitable trust (2018PG-t1d053). Organ Procurement Organizations partnering with nPOd to provide research resources are listed at www.jdrfnpod.org/for-partners/npod-partners. the content and views expressed are the responsibility of the authors and do not necessarily reflect an official view of nPOd. Author contributions: conceptualization: F.V., A.c., P.A., S.t., S.J.R., J.V., n.V.W.G., S.Y., A.P., h.h., t.R.-c., M.F.-t., and R.M. Methodology: F.V., A.c., d.K., Z.Z., P.A., S.t., O.B.-M., J.P.-h., B.B., G.A., c.h., J.K., S.c.K., M.n., S.J.R., J.V., Y.V., J.l., R.S., P.G., S.B., S.Y., A.P., h.h., t.R.-c., M.F.-t., and RM. Resources: d.K., Z.Z., P.A., S.t., i.S., B.B., G.A., J.K., M.n., S.J.R., J.V., Z.M., e.B., n.l., J.S., c.B., P.G., S.B., S.Y., A.P., t.R.-c., M.F.-t., and R.M. investigation: F.V., A.c., d.K., Z.Z., P.A., S.t., i.S., O.B.-M., J.P.-h., B.B., G.A., c.h., J.K., S.c.K., M.n., S.J.R., J.V., Y.V., J.l., M.S., J.S., P.G., A.P., h.h., t.R.-c., and R.M. Formal analysis: F.V., A.c., d.K., Z.Z., O.B.-M., i.S., J.P.-h., G.A., c.h., J.K., S.J.R., J.V., J.l., A.P., t.R.-c., and R.M. Software: A.c. data curation: d.K., Z.Z., J.K., S.J.R., M.F.-t., and R.M. Validation: F.V., A.c., d.K., Z.Z., P.A., S.t., O.B.-M., J.P.-h., J.K., S.c.K., S.J.R., J.V., Y.V., S.Y., t.R.-c., M.F.-t., and R.M. Visualization: F.V., A.c., d.K., Z.Z., P.A., O.B.-M., J.P.-h., G.A., c.h., J.K., S.J.R., t.R.-c., A.P., and R.M. Supervision: M.n., J.V., S.Y., A.P., t.R.-c., M.F.-t., and R.M. Funding acquisition: S.t., M.n., J.V., A.P., h.h., t.R.-c., M.F.-t., and R.M. Project administration: S.J.R., J.V., J.S., S.Y., A.P., M.F.-t., and RM. Writing—original draft: F.V., A.c., t.R.-c., M.F.-t., and R.M. Writing—review and editing: F.V., A.c., d.K., Z.Z., P.A., J.P.-h., M.n., S.J.R., J.V., S.Y., A.P., h.h., t.R.-c., and RM. Competing interests: h.h. is a board member and stock owner in Vactech ltd., which develops vaccines against picornaviruses and licensed cVB vaccine–related intellectual property rights to Provention Bio inc. A.P., h.h., and M.F.-t. have served on the scientific advisory board of Provention Bio inc. (acquired by Sanofi in 2023). R.M. received research funding from Provention Bio inc. All other authors declare they have no competing interests. Data and materials availability: immunopeptidomics datasets have been deposited under PRide: PXd042711. All other data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. All unique/stable reagents generated in this study can be provided by R.M. pending scientific review and a completed materials transfer agreement. Requests should be submitted to roberto.mallone@ inserm.fr.
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