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Phosphatidylserine-positive extracellular vesicles boost effector CD8⁺ T cell responses during viral infection.

ABSTRACT: CD8⁺ T cells are crucial for the clearance of viral infections. During the acute phase, proinflammatory conditions increase the amount of circulating phosphatidylserine⁺ (PS) extracellular vesicles (EVs). These EVs interact especially with CD8⁺ T cells; however, it remains unclear whether they can actively modulate CD8⁺ T cell responses. In this study, we have developed a method to analyze cell-bound PS⁺ EVs and their target cells in vivo. We show that EV⁺ cell abundance increases during viral infection and that EVs preferentially bind to activated, but not naive, CD8⁺ T cells. Superresolution imaging revealed that PS⁺ EVs attach to clusters of CD8 molecules on the T cell surface. Furthermore, EV-binding induces antigen (Ag)-specific TCR signaling and increased nuclear translocation of the transcription factor Nuclear factor of activated T-cells (NFATc1) in vivo. EV-decorated but not EV-free CD8⁺ T cells are enriched for gene signatures associated with T-cell receptor signaling, early effector differentiation, and proliferation. Our data thus demonstrate that PS⁺ EVs provide Ag-specific adjuvant effects to activated CD8⁺ T cells in vivo.

SUBMITTER: Rausch L

PROVIDER: S-EPMC10120060 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Phosphatidylserine-positive extracellular vesicles boost effector CD8+ T cell responses during viral infection.

Rausch Lisa L Flaskamp Lavinia L Ashokkumar Ashretha A Trefzer Anne A Ried Christine C Buchholz Veit R VR Obst Reinhard R Straub Tobias T Brocker Thomas T Kranich Jan J

Proceedings of the National Academy of Sciences of the United States of America 20230411 16

CD8+ T cells are crucial for the clearance of viral infections. During the acute phase, proinflammatory conditions increase the amount of circulating phosphatidylserine+ (PS) extracellular vesicles (EVs). These EVs interact especially with CD8+ T cells; however, it remains unclear whether they can actively modulate CD8+ T cell responses. In this study, we have developed a method to analyze cell-bound PS+ EVs and their target cells in vivo. W ...[more]

PMID: 37040405

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Project description:Under physiological conditions, phosphatidylserine (PS) predominantly localizes to the cytosolic leaflet of the plasma membrane of cells. During apoptosis, PS is exposed on the cell surface and serves as an "eat-me" signal for macrophages to prevent releasing self-immunogenic cellular components from dying cells which could potentially lead to autoimmunity. However, increasing evidence indicates that viable cells can also expose PS on their surface. Interestingly, tumor cell-derived extracellular vesicles (EVs) externalize PS. Recent studies have proposed PS-exposing EVs as a potential biomarker for the early detection of cancer and other diseases. However, there are confounding results regarding subtypes of PS-positive EVs, and knowledge of PS exposure on the EV surface requires further elucidation. In this study, we enriched small EVs (sEVs) and medium/large EVs (m/lEVs) from conditioned media of breast cancer cells (MDA-MB-231, MDA-MB-468) and non-cancerous cells (keratinocytes, fibroblasts). Since several PS-binding molecules are available to date, we compared recombinant proteins of annexin A5 and the carboxylated glutamic acid domain of Protein S (GlaS), also specific for PS, to detect PS-exposing EVs. Firstly, PS externalization in each EV fraction was analyzed using a bead-based EV assay, which combines EV capture using microbeads and analysis of PS-exposing EVs by flow cytometry. The bulk EV assay showed higher PS externalization in m/lEVs derived from MDA-MB-468 cells but not from MDA-MB-231 cells, while higher binding of GlaS was also observed in m/lEVs from fibroblasts. Second, using single EV flow cytometry, PS externalization was also analyzed on individual sEVs and m/lEVs. Significantly higher PS externalization was detected in m/lEVs (annexin A1+) derived from cancer cells compared to m/lEVs (annexin A1+) from non-cancerous cells. These results emphasize the significance of PS-exposing m/lEVs (annexin A1+) as an undervalued EV subtype for early cancer detection and provide a better understanding of PS externalization in disease-associated EV subtypes.

Dataset Information

Phosphatidylserine-positive extracellular vesicles boost effector CD8⁺ T cell responses during viral infection.

Publications

Phosphatidylserine-positive extracellular vesicles boost effector CD8<sup>+</sup> T cell responses during viral infection.

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