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

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.

SUBMITTER: Vecchio F

PROVIDER: S-EPMC10917340 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Coxsackievirus infection induces direct pancreatic β cell killing but poor antiviral CD8<sup>+</sup> T cell responses.

Vecchio Federica F Carré Alexia A Korenkov Daniil D Zhou Zhicheng Z Apaolaza Paola P Tuomela Soile S Burgos-Morales Orlando O Snowhite Isaac I Perez-Hernandez Javier J Brandao Barbara B Afonso Georgia G Halliez Clémentine C Kaddis John J Kent Sally C SC Nakayama Maki M Richardson Sarah J SJ Vinh Joelle J Verdier Yann Y Laiho Jutta J Scharfmann Raphael R Solimena Michele M Marinicova Zuzana Z Bismuth Elise E Lucidarme Nadine N Sanchez Janine J Bustamante Carmen C Gomez Patricia P Buus Soren S You Sylvaine S Pugliese Alberto A Hyoty Heikki H Rodriguez-Calvo Teresa T Flodstrom-Tullberg Malin M Mallone Roberto R

Science advances 20240306 10

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<sup>+</sup> T cells from CVB-seropositive individuals recognized a fraction of these peptides; only another subfraction was targeted ...[more]

PMID: 38446892

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Project description:BackgroundThe role of CD161 expression on CD8+ T cells in tumor immunology has been explored in a few studies, and the clinical significance of CD161+CD8+ T cells in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study seeks to clarify the prognostic value and molecular characteristics linked to CD161+CD8+ T cell infiltration in PDAC.MethodsThis study included 186 patients with confirmed PDAC histology after radical resection. CD161+CD8+ T cell infiltration was assessed using immunofluorescence staining on tumor microarrays. Flow cytometry and single-cell RNA sequencing were used to evaluate their functional status.ResultsWe observed significant associations between tumor-infiltrating CD161+CD8+ T cells and clinicopathological factors, such as tumor differentiation, perineural invasion, and serum CA19-9 levels. Patients with higher tumor-infiltrating CD161+CD8+ T cell levels had longer overall survival (OS) and recurrence-free survival (RFS) than those with lower levels. Multivariable analysis confirmed tumor-infiltrating CD161+CD8+ T cell as an independent prognostic indicator for both OS and RFS. Notably, a combination of tumor-infiltrating CD161+CD8+ T cell and CA19-9 levels showed a superior power for survival prediction, and patients with low tumor-infiltrating CD161+CD8+ T cell and high CA19-9 levels had the worst survival. Furthermore, lower tumor-infiltrating CD161+CD8+ T cells were associated with a better response to adjuvant chemotherapy. Finally, we identified tumor-infiltrating CD161+CD8+ T cells as a unique subtype of responsive CD8+ T cells characterized by increased levels of cytotoxic cytokines and immune checkpoint molecules.ConclusionCD161+CD8+ T cells exhibit elevated levels of both cytotoxic and immune-checkpoint molecules, indicating as a potential and attractive target for immunotherapy. The tumor-infiltrating CD161+CD8+ T cell is a valuable and promising predictor for survival and therapeutic response to adjuvant chemotherapy in PDAC. Further research is warranted to validate its role in the risk stratification and optimization of therapeutic strategies.

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

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Coxsackievirus infection induces direct pancreatic β cell killing but poor antiviral CD8<sup>+</sup> T cell responses.

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

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Coxsackievirus infection induces direct pancreatic β cell killing but poor antiviral CD8&lt;sup&gt;+&lt;/sup&gt; T cell responses.

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

Coxsackievirus infection induces direct pancreatic β cell killing but poor antiviral CD8<sup>+</sup> T cell responses.