T-cell-specific surface glycoprotein CD28 (CD28; TP44) is the first discovered costimulatory receptor expressed on T cells. It is expressed as a homodimer and it competes with CTLA-4 for its B7 ligands, CD80 and CD86, on antigen presenting cells. (1) Although CTLA-4 binding to both ligands is always stronger than CD28 binding, when in competition, CD86 has a relative preference for CD28 compared to CD80, which binds very strongly to CTLA-4. (2) CD28 drives important intracellular biochemical events such as unique phosphorylation and transcriptional signaling, production of key cytokines, chemokines and survival signals that are crucial for long-term expansion and differentiation of T cells. (2) Amount of CD28/Ligand binding versus CTLA-4/Ligand binding determines whether a T cell will undergo activation or anergy. (3) Additionally the third ligand for CD28 (and CTLA-4) was discovered, B7-H2 (ICOS Ligand), which primarily binds to ICOS. (4) ICOS binds to B7-H2 with significantly higher affinity than does CD28 or CTLA-4. (4) Since CD28 generates costimulatory signals in T cells, its antagonist, e.g. to prevent the progression of autoimmune diseases and organ graft rejections, as well as agonists, immune activators for the treatment of infectious diseases, are considered necessary. (2)

1. Lenschow DJ et al. CD28/B7 system of T cell costimulation. Annual Review of Immunology. 1996, Vol. 14, pp. 233–258.
2. Esensten JH et al. CD28 costimulation: from mechanism to therapy. Immunity. 2016, Vol. 44, 5, pp. 973–988.
3. Buchbinder EI and Desai A. CTLA-4 and PD-1 Pathways Similarities, Differences, and Implications of Their Inhibition. American Journal of Clinical Oncology. 2016, Vol. 39, 1, pp. 98-106.
4. Chen L and Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nature Reviews Immunology. 2013, Vol. 13, 4, pp. 227-242.