Regulating the discriminatory response to antigen by T-cell receptor

Abstract

The cell-mediated immune response constitutes a robust host defense mechanism to eliminate pathogens and oncogenic cells. T-cells play a central role in such a defense mechanism and creating memories to prevent any potential infection. T-cell recognizes foreign antigen by its surface receptors when presented through antigen-presenting cells and calibrates its cellular response by a network of intracellular signaling events. Activation of T-cell receptor (TCR) leads to changes in gene expression and metabolic networks regulating cell development, proliferation, and migration. TCR does not possess any catalytic activity, and the signaling initiates with the colocalization of several enzymes and scaffold proteins. Deregulation of T cell signaling is often linked to autoimmune disorders like SCID, Rheumatoid arthritis, and multiple sclerosis. The TCR remarkably distinguishes the minor difference between self and non-self antigen through a kinetic proofreading mechanism. The output of TCR signaling is determined by the half-life of the receptor-antigen complex and the time taken to recruit and activate the downstream enzymes. A longer half-life of a non-self antigen receptor complex could initiate downstream signaling by activating associated enzymes. Whereas, the short-lived self-peptide receptor complex disassembles before the downstream enzymes are activated. Activation of TCR rewires the cellular metabolic response to aerobic glycolysis from oxidative phosphorylation. How does the early event in the TCR signaling cross-talk with the cellular metabolism is an open question. In this review, we have discussed the recent developments in understanding the regulation of TCR signaling, and then we reviewed the emerging role of metabolism in regulating T-cell function.

Optical sensing and control of T cell signaling pathways

“…T cell receptors recognize a variety of antigens and initiate signaling pathways for adaptive immune responses ( Huse, 2009 ). The TCR complex is a sophisticated assembly of integral membrane proteins incorporating highly variable α and β chains, which noncovalently associated with CD3 signaling subunits γ, δ, ε, and ζ ( Choudhuri and van der Merwe, 2007 ; Xu et al, 2020 ; Gangopadhyay et al, 2022 ). TCR signaling pathways are initiated by the interaction between the α/β chains of the TCR complex and the antigen peptides presented on major histocompatibility complex (MHC) in antigen-presenting cells (APCs).…”

Immunotherapy: A new target for cancer cure (Review)

“…Immune cells comprise innate (dendritic (D) and natural killer (NK) cells and macrophages) and adaptive immune cells (T and B cells) ( 22 ). Immune molecules comprise membrane-type (such as T and B cell receptor (CR), adhesion and major histocompatibility complex (MHC) molecules and cytokine receptors) and secreted molecules (such as immunoglobulin, complement and cytokines) ( 23 , 24 ). The most important function of the innate immune system is to respond quickly to infection or inflammation and to recruit innate immune cells or activate complement via cytokines secreted by the injured site (such as ILs and chemokines) ( 25 ).…”