Immune Checkpoints: Novel Therapeutic Targets to Attenuate Sepsis-Induced Immunosuppression

Abstract

Sepsis is a leading cause of death in intensive care units and survivors develop prolonged immunosuppression and a high incidence of recurrent infections. No definitive therapy exists to treat sepsis and physicians rely on supportive care including antibiotics, intravenous fluids, and vasopressors. With the rising incidence of antibiotic resistant microbes, it is becoming increasingly critical to discover novel therapeutics. Sepsis-induced leukocyte dysfunction and immunosuppression is recognized as an important contributor towards increased morbidity and mortality. Pre-clinical and clinical studies show that specific cell surface inhibitory immune checkpoint receptors and ligands including PD-1, PD-L1, CTLA4, BTLA, TIM3, OX40, and 2B4 play important roles in the pathophysiology of sepsis by mediating a fine balance between host immune competency and immunosuppression. Pre-clinical studies targeting the inhibitory effects of these immune checkpoints have demonstrated reversal of leukocyte dysfunction and improved host resistance of infection. Measurement of immune checkpoint expression on peripheral blood leukocytes may serve as a means of stratifying patients to direct individualized therapy. This review focuses on advances in our understanding of the role of immune checkpoints in the host response to infections, and the potential clinical application of therapeutics targeting the inhibitory immune checkpoint pathways for the management of septic patients.

Keywords: T lymphocyte; immune checkpoints; immunosuppression; myeloid cell; sepsis.

Figure 1

Overview of the major immune cell checkpoints and associated signaling pathways. Antigen presentation via MHC on APCs to the TCR complex on T cells executes activation of T cells via Zap70 and ERK/MAPK signaling pathways. Ligation of CD28 on T cells with CD80/86 on APCs provides co-stimulatory signals. PD-1/PD-L and CTLA-4 signaling impair T cell activation via inhibition of the AKT signaling pathway. PD-1signaling involves SHP mediated inhibition of Zap20 and PI3K/AKT signaling pathway, whereas CTLA-4 directly inhibits the AKT pathway via recruiting PP2A. 2B4, TIM3, BTLA, and LAG-3 also inhibit T cell activation through interaction with their associated ligands on APCs. Ox40-Ox40L serves as a co-stimulatory signal for T cells via PI3K/AKT and NFkB pathways. Red lines represent inhibitory signals while green represents stimulatory signals. ITSM, ITIM, KIEELE represent specific intracellular domains of the immune checkpoints which mediate their intracellular signaling APC, antigen presenting cell; HVEM, herpes virus entry mediator; MHC, Major histocompatibility complex; BTLA, B and T lymphocyte attenuator; TIM3, T cell membrane protein-3; LAG-3, Lymphocyte activation-gene-3; TCR, T cell receptor; PD-1, Programmed death-1; CTLA4, Cytotoxic T lymphocyte antigen-4; ITSM, Immunoreceptor Tyrosine-based Motif; ZAP70, Zeta Chain of T Cell Receptor Associated Protein Kinase 70; PI3K, Phosphoinositide 3 kinase; ITIM, immunoreceptor tyrosine-based inhibition motif; SHP, Src homology region 2 domain-containing phosphatase; PP2A, protein phosphatase 2A; TRAF, TNF receptor associated factor; ERK, Extracellular signal-regulated kinase; MAPK, mitogen activated protein kinase; AKT, protein kinase B.