Abstract
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 immunity, 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). The number of 2W1S-specific memory CD4 T cells was significantly reduced on day 2 after sepsis induction, but recovered by day 14. In contrast to the transient numerical change, the 2W1S-specific memory CD4 T cells displayed prolonged functional impairment after sepsis, evidenced by a reduced recall response (proliferation and effector cytokine production) after restimulation with cognate Ag. To define the extent to which the observed functional impairments in the memory CD4 T cells impacts protection to secondary infection, B6 mice were infected with attenuated Salmonella enterica-2W (Se-2W) 30 days before sham or CLP surgery, and then challenged with virulent Se-2W after surgery. Pathogen burden was significantly higher in the CLP-treated mice compared to shams. Similar reductions in functional capacity and protection were noted for the endogenous OVA323-specific memory CD4 T cell population in sepsis survivors upon Lm-OVA challenge. 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.
Highlights
The importance of a functional immune system for overall health is dramatically illustrated by individuals with immune system defects being highly susceptible to serious and often life-threatening infections
delayed-type hypersensitivity (DTH) responses are driven in large part by memory CD4 T cells—even though other immune cells such as CD8 T cells and antigen presenting cells (APCs) participate in the response—and DTH can be used as an assessment of overall immune system fitness [38]
To more directly and rigorously interrogate the long-term consequences of sepsis on memory CD4 T cells, we used a protocol where an endogenous, Ag-specific memory CD4 T cell population was generated by infection with attenuated Listeria monocytogenes engineered to express the I-Ab-restricted peptide 2W1S (Lm-2W1S) 30 days before performing sham/cecal ligation and puncture (CLP) surgery (Figure 1A)
Summary
The importance of a functional immune system for overall health is dramatically illustrated by individuals with immune system defects being highly susceptible to serious and often life-threatening infections. Defined as a systemic inflammatory response syndrome during a disseminated infection [2, 3], early stages of sepsis are marked by a potentially fatal hyperinflammatory state driven by proinflammatory cytokines [4,5,6]. Concurrent with this hyperinflammation is system-wide transient loss of multiple immune cell types that decreases the ability of the septic host to respond to the primary infection or secondary nosocomial infection. The prolonged immune suppression that develops after a septic event is considered a leading reason for the extended period of increased susceptibility to pathogens normally handled by the immune system in healthy individuals [11, 12]
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