Platelet MHC class I mediates CD8+ T-cell suppression during sepsis

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-g 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 CD81 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 newmechanismby which platelets, through MHC-I, process and cross-present antigens, engage antigen-specific CD81 T cells, and regulate CD8(+) T-cell numbers, functional responses, and outcomes during sepsis.

Automated summary

The study revealed that during sepsis, platelets upregulate antigen cross-presentation through MHC-I, interacting with antigen-specific CD8(+) T cells and regulating CD8(+) T-cell numbers, functional responses, and outcomes.