Polymicrobial sepsis impairs antigen-specific memory CD4 T cell-mediated immunity

Abstract

Abstract Sepsis strikes 750,000 Americans annually. Patients who survive sepsis display prolonged immune dysfunction and heightened risk of secondary infection. CD4 T cells support a variety of cells required for protective immune responses, and perturbations to the CD4 T cell compartment can decrease overall immune system fitness. Using the cecal ligation and puncture (CLP) mouse model of sepsis, we investigated the impact of sepsis on endogenous Ag-specific memory CD4 T cells generated in C57Bl/6 (B6) mice infected with attenuated Listeria monocytogenes (LM) expressing the I-Ab-restricted 2W1S epitope (LM-2W). Sepsis transiently reduced the number of 2W1S-specific memory CD4 T cells on day 2, but numbers recovered by day 14. In contrast to the transient numerical change, there was prolonged impairment in the functional capacity of the 2W1S-specific memory CD4 T cells after sepsis, evidenced by a reduced recall response (proliferation and effector cytokine production) after restimulation with cognate Ag. We then assessed 2W1S-specific memory CD4 T cell-mediated protection to a secondary bacterial challenge after sepsis induction. B6 mice were infected with attenuated Salmonella-2W 30 days before sham or CLP surgery, and then challenged with virulent Salmonella-2W after surgery. Pathogen burden was significantly higher in the CLP-treated mice compared to shams. Similar reductions in functional capacity were noted for the endogenous OVA323–339-specific memory CD4 T cell population in septic mice. Our data collectively show CLP-induced sepsis alters the number and function of Ag-specific memory CD4 T cells, which contributes (in part) to the characteristic long-lasting immunoparalysis seen after sepsis.