Sepsis-Induced T Cell Immunoparalysis: The Ins and Outs of Impaired T Cell Immunity

Abstract

Sepsis results in a deluge of pro- and anti-inflammatory cytokines, leading to lymphopenia and chronic immunoparalysis. Sepsis-induced long-lasting immunoparalysis is defined, in part, by impaired CD4 and CD8 αβ T cell responses in the postseptic environment. The dysfunction in T cell immunity affects naive, effector, and memory T cells and is not restricted to classical αβ T cells. Although sepsis-induced severe and transient lymphopenia is a contributory factor to diminished T cell immunity, T cell-intrinsic and -extrinsic factors/mechanisms also contribute to impaired T cell function. In this review, we summarize the current knowledge of how sepsis quantitatively and qualitatively impairs CD4 and CD8 T cell immunity of classical and nonclassical T cell subsets and discuss current therapeutic approaches being developed to boost the recovery of T cell immunity postsepsis induction.

Figure 1. Naïve, effector, and memory T cells generated after acute infection/vaccination

Naïve T cells, of a given Ag-specificity, exist at low numbers with minimal on-per-cell basis functionality and protective capacity. They are long-lived cells able to vigorously proliferate upon cognate Ag-stimulation, generating a sizable effector pool with ample functionality (cytotoxicity and cytokine production) and protective capacity. However, the vast majority of effector T cells have a limited life-span with diminished Ag-driven proliferative capacity. Those effector T cells that survive the contraction phase will form a long-lived memory T cell pool maintaining their effector functionality and protective capability. ¹Of note - memory T cells represent a heterogeneous population of cells with defined phenotype, function, and localization that constantly changes with time after initial antigen encounter (93, 94). It is interesting to posit that memory T cell subsets might have differential susceptibility to sepsis-induced apoptosis and ability to recover in numbers and function in post-septic environment.

Figure 2. Sepsis-induced changes in naïve and memory T cells

Sepsis induces rapid and vigorous apoptosis of A) naïve (Ag-non experienced CD11a^low/CD8α^high CD8 or CD11a^low/CD49d^low CD4 T cells) T cells creating a lymphopenic environment supporting homeostatic proliferation (HP) of T cells that survive early ‘cytokine storm’ phase of sepsis. As a consequence of HP and in response to microbes that evoke sepsis, numerical recovery of T cell compartment is accompanied by phenotypic/functional changes (memory-like T cells) on a sizeable fraction of T cells. Sepsis can induce ‘holes’ in the T cell repertoire further contributing to overall changes in the composition of T cell pools, making their subsequent T cell responses to newly encountered pathogens potentially impaired. Similarly, B) pre-existing memory T cells (here, we are considering circulatory memory CD8 T cells) are also susceptible to sepsis-induced apoptosis leaving the host susceptible to pathogen re-encounter. The extent to which ‘bona fide’ memory T cell responses recover numerically and/or functionally is currently unknown but critical for our understanding of the sepsis-induced long-lasting immunoparalysis state. Of note, naïve and pre-existing memory T cell responses were modeled separately in A and B for clarity; however, the T cell compartment in any host experiencing sepsis will have both populations of CD4 and CD8 T cells simultaneously present. ¹Memory T cell responses of defined Ag-specificity generated after primary infection and/or vaccination that exist prior to septic insult; ²Memory-like cells (defined as CD11a^high/CD8α^low CD8 or CD11a^high/CD49d^high CD4 T cells) are those which acquire memory characteristics as a result of the septic event and potentially include both Ag-independent (HP) and Ag-dependent (pathogens that induce sepsis) T cell responses.

Figure 3. CD8 T cell-mediated immunity to localized re-infection diminished after sepsis in a multifactorial manner

A) Tissue resident memory CD8 T cells (T_RM) and circulating memory (T_CIRCM) CD8 T and B cells are evoked upon primary infection/immunization. B) ‘Moderate’ sepsis (that leads to 90%+ long-term survival) induces dramatic numerical loss of circulating but not resident CD8 T cell populations. C) Localized pathogen re-infection (or cognate Ag-encounter) of the healthy host induces the ‘sensing and alarm’ function of T_RM. As a consequence, the IFN-γ produced by T_RM acts on the local endothelium to upregulate chemokines and adhesion molecules (e.g., CXCL9 and VCAM1, respectively) promoting the influx of memory T and B cells from circulation and facilitating clearance of the pathogen in situ. D) ‘Moderate’ sepsis does not significantly impact the number and/or function of pre-existing T_RM responding to pathogen re-infection. However, endothelial cells are unable to respond to the IFN-γ signal and upregulate chemokines and adhesion molecules. Consequently, there is a dramatically reduced number of effector cells recruited from the circulation and pathogen clearance is significantly impaired.