Polymicrobial Sepsis Diminishes Dendritic Cell Numbers and Function Directly Contributing to Impaired Primary CD8 T Cell Responses In Vivo

Abstract

Patients surviving acute stages of sepsis often display impaired adaptive immune responses. Using the cecal ligation and puncture (CLP) model, we demonstrated that sepsis leads to substantial and long-lasting changes in the naïve CD8 T-cell repertoire affecting the capacity of the host to respond to new infections. However, the identity of CD8 T-cell extrinsic factor(s) and mechanism(s) that contribute to impaired CD8 T-cell responses after sepsis is currently unknown. Priming of naïve CD8 T-cells is critically dependent on the ability of dendritic cells (DCs) to provide Ag, co-stimulation, and inflammatory “signal 3” cytokines, therefore the sepsis-induced changes in the DC compartment might represent a contributing factor leading to diminished CD8 T-cell immunity in septic hosts. In a direct test of this hypothesis we show that in addition to numerical decline, sepsis leads to functional impairments in DCs diminishing their capacity to produce cytokines upon TLR stimulation in vitro or after infection in vivo. Importantly, we demonstrated a direct link between DC dysfunction and impairments in CD8 T-cell immunity after sepsis by directly targeting Ag to DCs. Finally, post-sepsis Flt3 ligand (Flt3L) treatment increased the number of DCs and improved DC function, including the ability to sense inflammation and produce IL-12 leading to improved primary CD8 T-cell responses to newly encountered antigens. Thus, sepsis-induced numerical and functional loss of DCs contributes to the observed defects in CD8 T-cell immunity, and therapeutic approaches designed to improve the status of the DC compartment after sepsis might facilitate the recovery of CD8 T-cell immunity.

Polymicrobial sepsis influences CD8 T cell responses and alters host susceptibility to infection and cancer

“…This finding is important given recent therapeutic strategies meant to restore number and/or function of memory CD8 T cells in septic patients, including cytokine therapy (IL-7 or IL-15) and checkpoint blockade (anti-PD-L1) (52,123,212). This report further supports the notion that merely focusing on fixing T cell impairments after sepsis induction may not fully restore CD8 T cell-mediated responses (73,181).…”

“…We and others have used the CLP model of sepsis because of its similarities to clinical manifestations of sepsis (55), and we have previously described how CLP-induced sepsis reduces the quantity and quality of naïve and memory CD4 and CD8 T cells (61,67,68,119,181). Moreover, we recently detailed how the consequences of sepsis on the number and function of dendritic cells contribute to the observed impairments in primary T cell responses (73). Thus, it is likely that intrinsic and extrinsic lesions contribute to the suboptimal T cell-dependent responses in septic hosts (181).…”

“…Some reports have already shown the potential of using outbred mice as an additional experimental tool in the context of sepsis research (67)(68)(69)(70)(71)(72)(73).…”

“…Polymicrobial sepsis also affects infection and/or vaccine-induced memory CD8 T cell responses by inducing apoptosis of pre-formed memory CD8 T cells and impairing the Ag-dependent andindependent memory CD8 T cell functions (e.g., functional avidity and IFN-γ production upon heterologous infection, respectively) (52,67,134). In addition to these T cellintrinsic factors affected in the post-septic host, deficiencies in T cell-extrinsic factors [e.g., dendritic cells (DC) capacity to provide 'signal 3' cytokines to promote optimal T cell responses], severely restrict the generation of productive T cell responses (73,181).…”

Crosstalk between Dendritic Cells and Immune Modulatory Agents against Sepsis

“…In low-income countries, the mortality rate as a result of septic shock and severe sepsis is almost 60% [1]. Apart from the short-term mortality of patients with sepsis, septic patients undergo plenty of long-term complications which will affect the quality of life and increase the five-year risk of death from subsequent of acute events [2][3][4].…”