Costimulatory receptor

Costimulatory receptors are a group of cell surface proteins that provide essential secondary signals for the activation, proliferation, and survival of lymphocytes, particularly T-cells (StatPearls, PMID: 30725820). These receptors are typically categorized into the Immunoglobulin (Ig) superfamily, such as CD28 and ICOS, and the Tumor Necrosis Factor Receptor (TNFR) superfamily, including 4-1BB (CD137), OX40 (CD134), CD27, and GITR (Nature Reviews Drug Discovery, doi:10.1038/nrd.2018.142). In the "two-signal" model of T-cell activation, Signal 1 is provided by the T-cell receptor (TCR) recognizing an antigen-MHC complex, while Signal 2 is provided by costimulatory receptors interacting with their ligands on antigen-presenting cells (PubMed, PMID: 23562315). These pathways are critical for preventing anergy and ensuring a robust immune response against pathogens and tumors (UniProt, P16410). In therapeutic contexts, agonists are being developed to stimulate these receptors to enhance anti-tumor immunity, while antagonists or decoy receptors (like CTLA-4-Ig) are used to treat autoimmune diseases and prevent transplant rejection by inhibiting these same pathways (FDA, Orencia Label). However, clinical development of costimulatory agonists has faced challenges, including systemic toxicity and cytokine release syndrome (Journal of Hematology & Oncology, doi:10.1186/s13045-018-0629-x).

Other names

Costimulatory moleculesT-cell costimulatory receptorsImmune costimulatory pathwaysPositive costimulatory moleculesSignal 2 receptors

Agonism of costimulatory receptors to enhance T-cell effector function and survival in oncology; Antagonism or ligand-masking to inhibit T-cell activation in autoimmunity and transplantation (Nature Reviews Drug Discovery, doi:10.1038/nrd.2018.142).