T-cell costimulatory receptor

T-cell costimulatory receptors are a group of cell-surface proteins that provide the essential 'second signal' required for the full activation, proliferation, and survival of T-lymphocytes following the recognition of an antigen (Signal 1). These receptors, which include members of the immunoglobulin superfamily (e.g., CD28, ICOS) and the tumor necrosis factor receptor (TNFR) superfamily (e.g., OX40, 4-1BB, CD27, GITR), interact with specific ligands that are upregulated on the surface of professional antigen-presenting cells, particularly dendritic cells, during an immune challenge (Chen and Flies, 2013, Nature Reviews Immunology [PMID: 23470321]). In the context of cancer, these pathways are often exploited by therapeutic agonistic antibodies to reinvigorate exhausted T-cells and enhance the anti-tumor immune response (Mellman et al., 2011, Nature [PMID: 22189301]). Conversely, in autoimmune diseases and organ transplantation, the costimulatory signal is targeted for inhibition—for example, by using CTLA-4-Ig fusion proteins like abatacept to block the CD28-CD80/86 interaction—to prevent pathological T-cell activation (Sharpe and Freeman, 2002, Nature Reviews Immunology [PMID: 11913069]). The therapeutic modulation of these receptors requires careful management due to the risk of systemic immune activation, such as cytokine release syndrome or organ-specific toxicities like hepatotoxicity (Ascierto et al., 2010, Journal of Translational Medicine [PMID: 20416094]).

Other names

Costimulatory moleculeSignal 2 receptorT-cell co-receptor

Agonism of costimulatory receptors to enhance T-cell activation; competitive inhibition of ligand binding to prevent costimulation.