Impairment and recovery of CD4 T cell-dependent B cell responses after sepsis

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Sepsis causes more deaths in U.S. hospitals annually than prostate cancer, breast cancer, and AIDS combined. Elderly patients are a particularly high-risk group, with an incidence rate of ~60% of all septic cases. The elderly are also extremely vulnerable to the consequences of sepsis, showing 100-fold higher mortality than younger patients. Some of these deaths occur acutely after sepsis, but ~70% of these patients survive the initial infection, and succumb to opportunistic infections during the chronic phase of sepsis. The chronic stage of sepsis is important and is characterized by immunosuppression, but little is known about the mechanisms of sepsis-induced immunosuppression. CD4 T cells, essential for coordinating immune responses to a range of pathogens, are severely depleted during the acute stage of sepsis, and gradually recover throughout the immunosuppressive phase of sepsis. Our recent publication included data showing certain Ag-specific CD4 T cell populations do not recover, despite quantitative restoration of total CD4 T cells. We suspect that the prolonged loss of Ag-specific CD4 T cells introduces “gaps” within the T cell repertoire leading to overall decreased adaptive immune system function. Among the immunological settings where CD4 T cell function is vital, this proposal will define the mechanisms responsible for the impairment of CD4 T cell-dependent B cell responses using the CLP model followed by secondary immunization or heterologous pathogen infection. Accordingly, our central hypothesis holds that alterations in the number and function of both follicular helper CD4 T (Tfh) cells and B cells after sublethal CLP-induced sepsis is responsible for suppressed humoral immunity and reduced protection against pathogens encountered within the context of localized or systemic secondary infections. The following specific aims will test our hypothesis: Aim 1) Define the sepsis-induced defects in Ag-specific CD4 T cells and B cells that restrict the generation of a productive CD4 T cell-dependent B cell response; Aim 2) Investigate the ability of therapies designed to restore DC or B cell number and function to revitalize humoral immunity after sepsis; and Aim 3) Determine the impact of sepsis on the maintenance and function of pre- existing memory CD4 T cells and B cells. Ultimately, this proposal will increase our understanding of why septic patients are more susceptible to secondary infections. Our use of the CLP model of polymicrobial sepsis, our ability to identify and study the function of endogenous Ag-specific CD4 T cells and B cells, and our experience measuring the adaptive immune response to infectious pathogens put us in the perfect position to define the mechanism(s) driving sepsis-induced suppression of CD4 T cell-dependent B cell immunity.