Sepsis inhibits pre-existing Ag-specific memory CD4 T cell-mediated immunity

Abstract

Abstract Sepsis strikes 750,000 Americans annually. Patients who survive severe sepsis display prolonged immune dysfunction with deficits in innate and adaptive immune responses. Thus, the most common cause of death of septic patients is the not from the initial septic event, but from a subsequent secondary infection. CD4 T cells support the function of a variety of immune cells needed during a productive and protective immune response, and perturbations in the CD4 T cell compartment can dramatically affect overall immune system fitness. Sepsis patients have defects in the DTH response, marked by a failure to respond to skin testing with Ag to which previous exposure is known to have occurred. Using the cecal ligation and puncture (CLP) mouse model of sepsis, we replicated this observation in CLP-treated mice. DTH is predominately mediated by CD4 T cells, bringing into question to what extent memory CD4 T cells are affected by sepsis. We observed rapid apoptosis of persisting memory Ag-specific CD4 T cells after sepsis induction. In addition to the numerical change in Agspecific CD4 T cells, sepsis altered Ag-specific functions of memory CD4 T cells. Specifically, Ag-specific CD4 T cells from CLP-treated mice produced significantly less effector cytokines (IFNγ, TNF, and IL-2) on a per cell basis after restimulation and their proliferative capacity was significantly decreased compared to the same Ag-specific population in sham-treated mice. These numerical and functional deficiencies in Ag-specific CD4 T cells in CLP-treated mice corresponded to a loss in CD4 T cell-mediated protection. Together, our data show CLP-induced sepsis impairs adaptive cellular immunity (in part) by affecting the number and function of Ag-specific memory CD4 T cells.