Understanding the Platelet-CD8+ T Cell Interactions in Sepsis

Abstract Sepsis remains a significant global health threat due to its high mortality rate and substantial economic burden. Nearly half of septic patients develop chronic critical illness (CCI), characterized by prolonged organ dysfunction and increased susceptibility to infections. T cell suppression, particularly CD8+ T cell suppression, is a key driver of CCI. Large gaps in understanding the pathogenesis of CCI have hindered its early identification and the development of effective therapies. Our recent work on platelets during sepsis revealed that major histocompatibility complex class I (MHC-I) antigen presentation and T cell regulating pathways are among the most significantly altered pathways in platelets. We further discovered that platelets actively internalize, degrade, and cross-present antigens via MHC-I to CD8+ T cells. Using platelet lineage specific MHC-I deficient mice, we found that platelet MHC-I plays a major role in CD8+ T cell suppression during sepsis. This research program further investigates the clinical impact of platelet mediated CD8+ T cell suppression and explores the mechanism of MHC- I mediated platelet–CD8+ T cell interactions in sepsis-associated CCI. The goals for our laboratory's research program over the next five years include the following: 1) determining whether platelet–CD8+ T cell aggregates are present in sepsis patients and whether they are associated with adverse outcomes; 2) characterizing which CD8+ T cell subsets are involved and how their functions differ from those of platelet-free CD8+ T cells; and 3) elucidating the structure and molecular mechanisms underlying these platelet-T cell interactions and their impact on CD8+ T cell function during sepsis. This research program addresses a critical gap in our understanding of sepsis pathogenesis. By investigating the previously unexplored relationship between MHC-I mediated platelets and CD8+ T cells, we aim to pave the way for improved long- term management strategies for sepsis.