부산대학교 도서관

Sepsis, an amplified immune response to systemic infection, is characterized by a transient cytokine storm followed by chronic immune dysfunction. Consequently, sepsis survivors are highly susceptible to newly introduced infections, suggesting sepsis can influence the function and composition of the naïve CD8 T cell pool and resulting pathogen-induced primary CD8 T cell responses. Here, we explored the extent to which sepsis induces phenotypic and functional changes within the naïve CD8 T cell pool. To interrogate this, the cecal ligation and puncture (CLP) mouse model of polymicrobial sepsis was used. In normal, non-septic mice, we show type-I interferon (IFN I)-mediated signaling plays an important role in driving the phenotypic and functional heterogeneity in the naïve CD8 T cell compartment leading to increased representation of Ly6C+ naïve CD8 T cells. In response to viral infection after sepsis resolution, naïve Ly6C+ CD8 T cells generated more primary effector and memory CD8 T cells with slower conversion to a central memory CD8 T cell phenotype (Tcm) than Ly6C- naïve CD8 T cells. Importantly, as a potent inducer of cytokine storm and IFN I production, sepsis leads to increased representation of Ly6C+ naïve CD8 T cells that maintained their heightened ability to respond (i.e., effector and memory CD8 T cell accumulation and cytokine production) to primary LCMV infection. Lastly, longitudinal analyses of peripheral blood samples obtained from septic patients revealed profound changes in CD8 T cell subset composition and frequency compared to healthy controls. Thus, sepsis has the capacity to alter the composition of naïve CD8 T cells, directly influencing primary CD8 T cell responses to newly introduced infections. Author summary: Sepsis is an exaggerated host response to systemic infection that can lead to significant mortality and long-lasting immune dysfunction in survivors. Sepsis-induced immune dysfunction contributes to the increased susceptibility to new infections and increased cancer incidence. These findings suggest naïve CD8 T cells are negatively impacted following a septic event, but the underlying mechanism(s) responsible for naïve CD8 T cell impairment and the consequences for CD8 T cell-mediated pathogen control remain understudied. Naïve CD8 T cells are required for the control of newly encountered pathogens and have been recently appreciated as a functionally and phenotypically heterogenous compartment. The present study defines Type I IFN as a signal which shapes naïve CD8 T cell heterogeneity at homeostasis. Following a septic event, the naïve CD8 T cell compartment undergoes lasting phenotypic and functional changes in mice and humans. Type I IFN signaling along with increased cell cycling in the post-septic environment contribute to this compositional change, which may have direct implications for therapeutic intervention to enhance CD8 T cell function in immunocompromised sepsis survivors. [ABSTRACT FROM AUTHOR]