Targeting Immune Cell Checkpoints during Sepsis

Abstract

Immunosuppression is increasingly being recognized as one of the causes of increased morbidity and mortality during sepsis. Both innate and adaptive immune system dysfunction have been shown to cause an impaired ability to eradicate the primary infection and also lead to frequent occurrence of secondary opportunistic infections. Pre-clinical and clinical studies have shown that inhibitory immune checkpoint molecules, including programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), cytotoxic T lymphocyte antigen-4 (CTLA-4), T cell membrane protein-3 (TIM-3), Lymphocyte activation-gene-3 (LAG-3) and 2B4, are upregulated during the course of sepsis. Engagement of these inhibitory molecules on various immune cells has been consistently shown to inhibit innate immune cell functions (e.g., phagocytosis, cytokine production and pathogen clearance) and also lead to impaired T cell competence. In numerous pre-clinical models of sepsis, therapeutic agents aimed at blocking engagement of inhibitory immune checkpoints on immune cells have been shown to improve innate and adaptive immune cell functions, increase host resistance to infection and significantly improve survival. Therefore, immunotherapy with immune cell checkpoint inhibitors holds significant potential for the future of sepsis therapy and merits further investigation.

Keywords: 2B4; BTLA; CTLA-4; LAG-3; PD-1; PD-L1; T cell exhaustion; TIM-3; immunosuppression; immunotherapy; myeloid cells; sepsis.

Figure 1

Inhibitory immune checkpoints on immune cells. Interaction among immune cell checkpoint receptors on T cells and antigen presenting cells (APCs) or target cells such as peripheral tissue epithelial cells inhibit leukocyte functions and may contribute to immune dysfunction. PD-1 = Programmed death-1; PD-L1 = Programmed death ligand-1; CTLA-4 = Cytotoxic T lymphocyte antigen-4; BTLA = B and T lymphocyte attenuator; HVEM = Herpes virus entry mediator; TIM-3 = T cell membrane protein-3; LAG-3 = Lymphocyte activation-gene-3; CEACAM = carcinoembryonic antigen-related cell adhesion molecule; MHC II = Major histocompatibility complex II.

Figure 2

Graphical representation of PD-1–PD-L1 interaction leading to immune cell dysfunction and immunosuppression. PD-1–PD-L1 interaction leads to impaired T cell function (exhaustion) and antigen presenting cell (myeloid) dysfunction. Antibodies targeting each of these inhibitory molecules reverse sepsis induced immunosuppression and improve host resistance to infection. (M = antigen presenting or myeloid cell; PD-1 = Programmed cell death-1; PD-L1 = Programmed cell death ligand-1; IFN-γ = interferon-gamma; IL-2 = interleukin-2; IL-6 = inerleukin-6, upward arrows indicates an increase and downward arrows indicates a decrease).