Costimulatory

Costimulatory refers to a set of molecular signals that accompany antigen recognition by T cells to achieve full activation. In the classical two-signal model of T cell activation, Signal 1 is delivered when the T cell receptor recognizes a peptide bound to an MHC molecule; Signal 2, the costimulatory signal, is provided by interactions between receptors on T cells and ligands on antigen-presenting cells. Costimulation shapes the magnitude, quality, and outcome of the immune response, influencing clonal expansion, cytokine production, differentiation, and memory formation. Absence of costimulation can lead to anergy, deletion, or tolerance rather than productive activation.

Positive costimulatory pathways include CD28 binding to CD80 or CD86 on antigen-presenting cells, as well as other receptors such as ICOS, 4-1BB (CD137), OX40 (CD134), CD27, and GITR, which enhance T cell responses. Negative or inhibitory costimulation helps restrain activation; the best characterized examples are CTLA-4, which binds CD80/CD86 with higher affinity than CD28, and PD-1, which engages PD-L1/PD-L2. The balance between these signals modulates the strength and duration of the response and contributes to peripheral tolerance.

Clinical relevance is substantial. Therapeutic strategies include costimulation blockade (for example, abatacept, a CTLA-4–Ig fusion protein that prevents CD28 engagement) used in autoimmune diseases, and checkpoint inhibitors such as anti-CTLA-4 or anti-PD-1/PD-L1 antibodies that release inhibitory brakes to boost anti-tumor immunity. Costimulation also informs vaccine design and transplantation tolerance, where deliberate modulation of these signals can shape outcomes.