Clinical and Experimental Sepsis Impairs CD8 T-Cell-Mediated Immunity

Abstract

Septic patients experience chronic immunosuppression resulting in enhanced susceptibility to infections normally controlled by T cells. Clinical research on septic patients has shown increased apoptosis and reduced total numbers of CD4 and CD8 T cells, suggesting contributing mechanism driving immunosuppression. Experimental models of sepsis, including cecal ligation and puncture, reverse translated this clinical observation to facilitate hypothesis-driven research and allow the use of an array of experimental tools to probe the impact of sepsis on T-cell immunity. In addition to numerical loss, sepsis functionally impairs the antigen-driven proliferative capacity and effector functions of CD4 and CD8 T cells. Sepsis-induced impairments in both the quantity and quality of T cells results in reduced protective capacity and increased susceptibility of mice to new or previously encountered infections. Therefore, the combined efforts of clinical and experimental sepsis research have begun to elucidate the impact of sepsis on T-cell-mediated immunity and potential T-cell-intrinsic and -extrinsic mechanisms driving chronic immunosuppression. Future work will explore the impact of sepsis on the recently appreciated tissue-resident memory (TRM) T cells, which provide robust protection against localized infections, and dendritic cells, which are needed to activate T cells and promote effective T-cell responses.

FIG. 1

Distinct phases of the primary CD8 T-cell responses upon antigen encounter. A, Naive CD8 T cells encounter cognate Ag and appropriate signals and promote their activation and accumulation during the vigorous primary expansion phase. Upon completion of the expansion, effector CD8 T cells undergo a programmed contraction (death) phase, which leaves a stable number of memory CD8 T cells that can be maintained for the life of the host and rapidly undergo secondary expansion upon Ag re-encounter. B, Functional properties of naive, effector and memory CD8 T cells. Naive CD8 T cells do not possess effector functions, but, upon exposure to cognate Ag, this population has the capacity to undergo proliferative expansion in numbers. Effector and memory CD8 T cells possess effector functions (cytokine secretion and cytolytic capacity) that mediate host protection. Vaccination or infection-generated memory CD8 T cells exposed to cognate Ag possess the capacity to undergo proliferative expansion and gain effector functions, providing rapid protection to the host upon re-infection. (Figure adapted with permission from Badovinac et al, 2006.).

FIG. 2

Proposed interplay of clinical and experimental research to elucidate the impact of sepsis on T-cell-mediated immunity. A, Clinical research on septic patients has shown increased apoptosis and reduced numbers of CD4 and CD8 T cells. B, Clinical observations of sepsis-induced apoptosis were successfully reverse translated in an experimental model (e.g., CLP). C, Experimental models could allow sepsis researchers to pursue hypothesis-driven research and utilize an array of experimental tools that are not feasible with human patients. The ultimate goal of experimental models is to translate hypotheses to human septic patients to further test hypotheses incorporating an array of biological and pathological heterogeneity. (Figure adapted with permission from Efron et al, 2015.).

FIG. 3

Sepsis affects the number of naive and memory CD8 T cells, influencing their ability to respond to secondary infection. Naive and primary memeory Ag-specific CD8 T cells undergo numerical loss shortly after sepsis induction. Due to their decreased numbers and/or impaired per-cell functionality, the magnitude of primary and secondary CD8 T-cell expansion is diminished in the septic host after secondary infection.

FIG. 4

T-cell-extrinsic factors mediate effective CD8 T-cell responses. The expansion of Ag-specific CD8 T cells is dependent on APCs (DCs) providing Ag:MHC (signal 1), co-stimulation (signal 2), and signal 3 cytokines (e.g. IL-12). Lack of signal 3 cytokine will lead to suboptimal CD8 T-cell expansion, reducing the effectiveness of the T-cell response. Sepsis-induced impairments of DCs’ ability to provide signals 1–3 could be an important mechanism behind the observed deficits in CD8 T-cell immunity after a septic event. (Figure adapted with permission from Haring et al., 2006.).