Immunometabolic Regulations Mediated by Coinhibitory Receptors and Their Impact on T Cell Immune Responses

Abstract

Host immunity provides wide spectrum protection that serves to eradicate pathogens and cancer cells, while maintaining self-tolerance and immunological homeostasis. Ligation of the T cell receptor (TCR) by antigen activates signaling pathways that coordinately induce aerobic glycolysis, mitochondrial activity, anabolic metabolism, and T effector cell differentiation. Activation of PI3K, Akt, and mTOR triggers the switch to anabolic metabolism by inducing transcription factors such as Myc and HIF1, and the glucose transporter Glut1, which is pivotal for the increase of glucose uptake after T cell activation. Activation of MAPK signaling is required for glucose and glutamine utilization, whereas activation of AMPK is critical for energy balance and metabolic fitness of T effector and memory cells. Coinhibitory receptors target TCR-proximal signaling and generation of second messengers. Imbalanced activation of such signaling pathways leads to diminished rates of aerobic glycolysis and impaired mitochondrial function resulting in defective anabolic metabolism and altered T cell differentiation. The coinhibitory receptors mediate distinct and synergistic effects on the activation of signaling pathways thereby modifying metabolic programs of activated T cells and resulting in altered immune functions. Understanding and therapeutic targeting of metabolic programs impacted by coinhibitory receptors might have significant clinical implications for the treatment of chronic infections, cancer, and autoimmune diseases.

β-Adrenergic signaling blocks murine CD8+ T-cell metabolic reprogramming during activation: a mechanism for immunosuppression by adrenergic stress

“…Another important direction will be to determine if the effects of β-adrenergic signaling on metabolism that we found in vitro also occur in the tumor microenvironment. While ligation of the TCR and costimulatory receptors drives metabolic reprogramming, ligation of coinhibitory receptors such as PD-1 has the opposite effect, decreasing glycolysis and mitochondrial function(34). Therefore, it will be important to investigate how adrenergic signaling affects these coinhibitory receptors.…”

Trial watch: chemotherapy-induced immunogenic cell death in immuno-oncology

“…tissue) tolerance; [77][78][79][80][81][82][83][84][85][86] (3) the relatively limited avidity of TAA-specific (and sometimes also TSA-specific) TCRs; [87][88][89][90][91][92][93][94][95][96] and (4) the ability of cancer cells to compromise cellular fitness and/or effector functions of T cells, hence driving 'exhaustion' or 'anergy'. [97][98][99][100][101][102][103][104][105][106][107][108][109] Two main criteria should be met for any treatment modality to be classified as a bona fide ICD inducer. 20,110 First, ICD-eliciting agents must exhibit superior therapeutic efficacy when employed against mouse tumors growing in immunocompetent, syngeneic (as compared to immunodeficient) hosts.…”

Immunotherapies for malignant glioma

“…Although CD28 serves as the prototype co-stimulatory whereas CTLA-4 and PD-1 serve as the prototype co-inhibitory receptors that regulate the outcome of T cell immune responses, it is now clear that numerous receptor ligand pairs on the surface of T cells and APC serve similar functions ( Figure 2 ) (recently reviewed in 131 ). The evolutional requirement for the multiple checkpoint pathways is not entirely understood but it is possible that such pathways differentially dominate responses in the context of different microenvironments, in the presence of different antigens or at distinct phases of T cell activation at which they are differentially expressed.…”