T-cell costimulation is the provision of additional activating signals that complement recognition of an antigen by a T cell. These signals help determine whether antigen recognition produces sustained activation, proliferation, and functional differentiation. The best-characterized pathway involves the T-cell receptor CD28 and its binding partners CD80 and CD86 on antigen-presenting cells. Costimulation is a central regulatory component of adaptive immunity, linking antigen specificity to the conditions under which an immune response develops. (ncbi.nlm.nih.gov)
Antigen recognition and the two-signal model
The classical two-signal model distinguishes antigen-specific recognition from accessory stimulation. Signal 1 originates when the T-cell receptor recognizes an antigen-derived peptide displayed by a major histocompatibility complex molecule. Signal 2 is supplied by costimulatory receptor–ligand interactions, particularly CD28 binding to B7-family molecules. During initial activation, an antigen-presenting cell, usually a dendritic cell, can provide both signals. This arrangement allows antigen recognition and accessory stimulation to be integrated during the same cellular encounter. (ncbi.nlm.nih.gov)
The model is a useful framework rather than a complete description of T-cell activation. Cytokines supply further information that influences growth and differentiation; these influences are often described as a third signal. Antigen recognition, costimulation, and cytokine exposure therefore contribute different kinds of information rather than acting as interchangeable stimuli. Their combined effects determine the magnitude and character of the developing response. (ncbi.nlm.nih.gov)
The CD28–CD80/CD86 pathway
CD28 is a cell-surface receptor expressed on naïve T cells. Its principal physiological binding partners are CD80, also called B7-1, and CD86, also called B7-2. These ligands also bind the inhibitory receptor CTLA-4, making their availability important for both activation and restraint. Although CD80 and CD86 share receptor partners, experiments demonstrate differences in their interactions with CTLA-4 and in the subsequent trafficking of receptor–ligand complexes. (ncbi.nlm.nih.gov)
CD28 engagement reinforces responses initiated through the T-cell receptor. It promotes cytokine production, proliferation, differentiation, and metabolic adaptation rather than supplying antigen specificity itself. One important consequence is increased production of interleukin-2, which supports activated T-cell growth. These effects explain why recognition of an appropriate antigen does not, by itself, reliably produce the same response as recognition accompanied by costimulation. (pmc.ncbi.nlm.nih.gov)
Intracellular signaling and metabolism
Costimulation changes the intracellular programs needed to sustain an immune response. Experimental studies have shown that CD28 signaling through phosphatidylinositol 3-kinase and Akt promotes increased glucose uptake and glycolysis. This metabolic response accompanies the increased biosynthetic and energetic demands associated with cellular growth, proliferation, and differentiation. Costimulation thus affects not only whether a T cell responds, but also its capacity to support a sustained response metabolically. (pubmed.ncbi.nlm.nih.gov)
Antigen-receptor stimulation without appropriate accessory signals can instead produce clonal anergy, a state of reduced responsiveness upon subsequent stimulation. Experiments with resting human T cells demonstrated that stimulation through immobilized anti-CD3 antibodies could induce later hyporesponsiveness, whereas inclusion of accessory signals prevented this outcome under the tested conditions. Such findings support the distinction between receptor engagement and productive activation and help explain one mechanism relevant to peripheral immune tolerance. (pubmed.ncbi.nlm.nih.gov)
Other costimulatory pathways
CD28 is not the only costimulatory receptor. Inducible T-cell costimulator (ICOS) is related to CD28 but binds a distinct ligand, ICOS ligand, historically called B7-related protein-1. ICOS expression increases following T-cell activation, and its functions are not identical to those of CD28. Studies identifying the ICOS–ligand pair showed that it could costimulate T cells independently of the CD28–B7 pathway. (nature.com)
Genetic experiments in ICOS-deficient mice established its importance for effective interactions between T cells and B cells. These animals exhibited impaired germinal-center formation and defective immunoglobulin class switching, demonstrating that costimulation can shape antibody responses as well as T-cell expansion. Different costimulatory pathways therefore have overlapping but non-equivalent biological roles. (nature.com)
Regulation by inhibitory receptors
Costimulation is balanced by inhibitory pathways associated with immune checkpoints. CTLA-4 shares CD80 and CD86 with CD28. One experimentally demonstrated mechanism of CTLA-4 action is trans-endocytosis: a CTLA-4-expressing cell captures these ligands from an opposing cell and internalizes them for degradation. Their removal reduces the ligands available to stimulate CD28. This provides a mechanism by which regulatory T cells can modify the stimulatory capacity of antigen-presenting cells. (pubmed.ncbi.nlm.nih.gov)
PD-1 can also inhibit costimulatory signaling. Biochemical reconstitution and cellular experiments demonstrated that PD-1-associated phosphatase activity can preferentially dephosphorylate CD28 under the conditions studied. This finding connects inhibitory checkpoint signaling directly to the regulation of a costimulatory receptor, although it does not make CD28 the sole target of PD-1 in every biological setting. (pmc.ncbi.nlm.nih.gov)
Clinical and experimental applications
Costimulation blockade is an established approach to immune modulation. Abatacept binds CD80 and CD86, preventing their interaction with CD28; it is used for conditions including rheumatoid arthritis. The related fusion protein belatacept blocks the same pathway and is used to prevent transplant rejection in adult kidney-transplant recipients. Their mechanism targets an accessory activation pathway rather than antigen recognition itself. (dailymed.nlm.nih.gov)
Costimulatory signaling is also incorporated into engineered receptors used in cancer immunotherapy. Chimeric antigen receptor T-cell designs can combine antigen recognition and CD3-zeta signaling with intracellular costimulatory domains derived from CD28 or 4-1BB. These domains influence activation and cellular behavior; experimental comparisons show that their effects depend on receptor design and signaling context, rather than one domain being universally superior. (cancer.gov)