| Autor: |
Guo, Li, Shen, Sikui, Rowley, Jesse W., Tolley, Neal D., Jia, Wenwen, Manne, Bhanu Kanth, McComas, Kyra N., Bolingbroke, Ben, Kosaka, Yasuhiro, Krauel, Krystin, Denorme, Frederik, Jacob, Shancy P., Eustes, Alicia S., Campbell, Robert A., Middleton, Elizabeth A., He, Xiao, Brown, Samuel M., Morrell, Craig N., Weyrich, Andrew S., Rondina, Matthew T. |
| Zdroj: |
Blood; August 2021, Vol. 138 Issue: 5 p401-416, 16p |
| Abstrakt: |
Circulating platelets interact with leukocytes to modulate host immune and thrombotic responses. In sepsis, platelet-leukocyte interactions are increased and have been associated with adverse clinical events, including increased platelet–T-cell interactions. Sepsis is associated with reduced CD8+T-cell numbers and functional responses, but whether platelets regulate CD8+T-cell responses during sepsis remains unknown. In our current study, we systemically evaluated platelet antigen internalization and presentation through major histocompatibility complex class I (MHC-I) and their effects on antigen-specific CD8+T cells in sepsis in vivo and ex vivo. We discovered that both human and murine platelets internalize and proteolyze exogenous antigens, generating peptides that are loaded onto MHC-I. The expression of platelet MHC-I, but not platelet MHC-II, is significantly increased in human and murine platelets during sepsis and in human megakaryocytes stimulated with agonists generated systemically during sepsis (eg, interferon-γ and lipopolysaccharide). Upregulation of platelet MHC-I during sepsis increases antigen cross-presentation and interactions with CD8+T cells in an antigen-specific manner. Using a platelet lineage–specific MHC-I–deficient mouse strain (B2Mf/f-Pf4Cre), we demonstrate that platelet MHC-I regulates antigen-specific CD8+T-cell proliferation in vitro, as well as the number and functional responses of CD8+T cells in vivo, during sepsis. Loss of platelet MHC-I reduces sepsis-associated mortality in mice in an antigen-specific setting. These data identify a new mechanism by which platelets, through MHC-I, process and cross-present antigens, engage antigen-specific CD8+T cells, and regulate CD8+T-cell numbers, functional responses, and outcomes during sepsis. |
| Databáze: |
Supplemental Index |
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