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

Area of Science:

• Immunology
• Hematology
• Sepsis Pathophysiology

Background:

• Platelet-leukocyte interactions are heightened in sepsis, influencing immune and thrombotic responses.
• Sepsis is linked to diminished CD8+ T-cell numbers and function, but platelet regulation remains unclear.
• Platelet-T-cell interactions are increased in sepsis, suggesting a role in disease progression.

Purpose of the Study:

• To investigate platelet antigen internalization and presentation via Major Histocompatibility Complex class I (MHC-I) in sepsis.
• To determine the impact of platelet MHC-I on antigen-specific CD8+ T cells during sepsis.
• To elucidate the role of platelet MHC-I in regulating CD8+ T-cell responses and sepsis outcomes.

Main Methods:

• Systemic evaluation of platelet antigen processing and MHC-I presentation in human and murine sepsis models (in vivo and ex vivo).
• Analysis of MHC-I and MHC-II expression on platelets and megakaryocytes under sepsis-related stimuli (interferon-γ, lipopolysaccharide).
• Utilized a platelet lineage-specific MHC-I-deficient mouse model (B2Mf/f-Pf4Cre) to assess CD8+ T-cell responses and sepsis mortality.

Main Results:

• Human and murine platelets internalize and proteolyze exogenous antigens, loading peptides onto MHC-I.
• Platelet MHC-I expression significantly increases during sepsis, enhancing antigen cross-presentation to CD8+ T cells.
• Loss of platelet MHC-I impairs antigen-specific CD8+ T-cell proliferation and function, reducing sepsis mortality in mice.

Conclusions:

• Platelets actively process and present antigens via MHC-I during sepsis, engaging antigen-specific CD8+ T cells.
• Platelet MHC-I is a key regulator of CD8+ T-cell numbers, function, and overall outcomes in sepsis.
• Targeting platelet MHC-I interactions offers a potential therapeutic strategy for sepsis management.