open access publication

Article, 2024

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

Science Advances, ISSN 2375-2548, Volume 10, 10, Page eadl1122, 10.1126/sciadv.adl1122

Contributors

Vecchio, Federica [1] Carré, Alexia 0000-0001-8144-7194 [1] Korenkov, Daniil A 0000-0001-8321-778X [1] Zhou, Zhicheng 0000-0001-9137-7951 [1] Apaolaza, Paola Stephanie 0000-0002-7550-054X [2] [3] Tuomela, Soile [4] [5] Burgos-Morales, Orlando 0000-0002-5086-2675 [1] Snowhite, Isaac V [6] [7] Perez-Hernandez, Javier [1] Brandao, Barbara [1] Afonso, Georgia [1] Halliez, Clémentine 0000-0002-5683-515X [1] [8] Kaddis, John S 0000-0002-6752-7670 [6] Kent, Sally Choate 0000-0002-1543-8086 [9] Nakayama, Maki [10] Richardson, Sarah J. [11] Vinh, Joëlle 0000-0001-7184-2668 [12] Verdier, Yann 0000-0002-3319-0053 [12] Laiho, Jutta E 0000-0002-5443-4651 [13] Scharfmann, Raphael 0000-0001-7619-337X [1] Solimena, Michele 0000-0002-3653-8107 [2] [14] Marinicova, Zuzana [2] [14] Bismuth, Elise [15] Lucidarme, Nadine [16] Sanchez, Janine [17] Bustamante, Carmen [17] Gomez, Patricia [17] Buus, Soeren 0000-0001-8363-1999 [18] Group, the nPOD-Virus Working You, Sylvaine 0000-0002-1578-5205 [1] [19] Pugliese, Alberto 0000-0002-7211-0319 [6] [7] Hyöty, Heikki A 0000-0003-0370-4145 [13] [20] [21] Rodriguez-Calvo, Teresa 0000-0003-1531-8583 [2] [3] Flodström-Tullberg, Malin A K 0000-0003-2685-2052 [4] [5] Mallone, Roberto 0000-0002-9846-8861 (Corresponding author) [1] [8] [19]

Affiliations

  1. [1] Institut Cochin
    2. [NORA names: France; Europe, EU; OECD];
  2. [2] German Center for Diabetes Research
    3. [NORA names: Germany; Europe, EU; OECD];
  3. [3] Helmholtz Zentrum München
    4. [NORA names: Germany; Europe, EU; OECD];
  4. [4] Karolinska Institutet
    5. [NORA names: Sweden; Europe, EU; Nordic; OECD];
  5. [5] Karolinska University Hospital
    6. [NORA names: Sweden; Europe, EU; Nordic; OECD];

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.

Keywords

B cells, B-cell killing, CD8+ T cell responses, CD8<sup>+</sup> T cells, GAD, PD-1, T cell responses, T cells, antigen, antiviral CD8+ T cell responses, autoimmunity, biomarkers, cells, circulating CD8<sup>+</sup> T cells, coxsackievirus, coxsackievirus B, coxsackievirus infection, data, differentiation, effector/memory T cells, epitopes, epitopes cross-reactive, ex vivo data, exhaustion marker PD-1, filopodia, fraction, human B cells, human leukocyte antigen, in vitro, individuals, infected B cells, infection, killing, leukocyte antigen, pancreatic B-cells, peptide, prevention, propagate infection, rationale, response, response to infection, subfractions, trials, type, type 1 diabetes, type 1 diabetes prevention, vaccine, vaccine trials, viral peptides

Funders

  • National Institute of Diabetes and Digestive and Kidney Diseases
  • Inserm
  • Swedish Research Council
  • Leona M. and Harry B. Helmsley Charitable Trust
  • Federal Ministry of Education and Research
  • Juvenile Diabetes Research Foundation
  • Sanofi (United States)
  • Novo Nordisk (Denmark)
  • European Commission
  • Agence Nationale de la Recherche
  • Fondation pour la Recherche Médicale
  • Scripps (United States)

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