T-cell-mediated immunity and the role of TRAIL in sepsis-induced immunosuppression

Abstract

Sepsis is the leading cause of death in most intensive care units, and the death of septic patients usually does not result from the initial septic event but rather from subsequent nosocomial infections. Patients who survive severe sepsis often display severely compromised immune function. Not only is there significant apoptosis of lymphoid and myeloid cells that depletes critical components of the immune system during sepsis, there is also decreased function of the remaining immune cells. Studies of animals and humans suggest the immune defects that occur during sepsis may be critical to pathogenesis and subsequent mortality. This review focuses on sepsis-induced alterations with the cluster differentiation (CD) 8 T-cell compartment that can affect the control of secondary heterologous infections. Understanding how a septic event directly influences CD8 T-cell populations through apoptotic death and homeostatic proliferation and indirectly by immune-mediated suppression will provide valuable starting points for developing new treatment options.

Figure 1. Primary CD8 T-cell responses to infection

An antigen-specific naïve CD8 T-cell becomes fully activated (Phase I) after interacting with an antigen-presenting cell (i.e., dendritic cell (DC)) presenting cognate antigen on MHC I to the T-cell receptor of a CD8 T-cell. Once activated, CD8 T-cells undergo rapid proliferative expansion (Phase II) resulting in the generation of effector CD8 T-cells that are able to secrete cytokines to combat the invading pathogen. Following the peak of expansion, CD8 T-cells undergo a contraction phase (Phase III) whereby 90–95% of responding effector cells will die. The remaining 5–10% cells transit into long-lived memory CD8 T-cells (Phase IV).

Figure 2. Sepsis-induced lymphocyte apoptosis changes the composition of the naïve CD8 T-cell repertoire

The naïve CD8 T-cell repertoire is composed of relatively small numbers of single antigen-specific naïve CD8 T-cell precursors that enable the host to respond to virtually any pathogen encounter. The impact of sepsis-induced apoptosis on particular antigen-specific naïve CD8 T-cell precursors likely occurs stochastically. Depicted in A, B and C are several scenarios that may occur following sepsis-induced lymphocyte apoptosis. A. Incomplete recovery of naïve CD8 T-cell precursors specific for antigen-(A) after sepsis. B. Complete recovery of naïve CD8 T-cell precursors specific for antigen-(B) after sepsis. C. Outgrowth of naïve CD8 T-cell precursors specific for antigen-(C) after sepsis. Taken together these scenarios illustrate that sepsis could alter the composition of the naïve CD8 T-cell repertoire which may have consequences on CD8 T-cell responses to infection.

Figure 3. Sepsis-induced homeostatic proliferation changes the phenotype of naïve CD8 T-cells

A lymphopenic environment is created after sepsis-induced lymphocyte apoptosis. The remaining naïve CD8 T-cells present replenish the environment via lymphopenia-induced homeostatic proliferation. As a consequence, CD8 T-cell numerical recovery is accompanied by a phenotypic change in naïve CD8 T-cells through increased expression of cell surface molecules (such as CD44, CD11a, CD122, Ly6c), resulting a ‘memory-like’ phenotype.