T-cell-specific surface glycoprotein CD28 and Cytotoxic T-lymphocyte protein 4 (CD28/CTLA-4)

The CD28 and CTLA-4 receptors constitute a critical regulatory axis in T-cell biology, governing the balance between immune activation and tolerance (nih.gov, 1.2.2). CD28 is constitutively expressed on T cells and provides the essential co-stimulatory signal (Signal 2) upon binding to CD80 or CD86 on antigen-presenting cells, which is necessary for full T-cell activation, proliferation, and survival (rndsystems.com, 1.1.1). In contrast, CTLA-4 (CD152) is upregulated following T-cell activation and serves as a potent inhibitory checkpoint by competing for the same B7 ligands with significantly higher affinity and avidity, thereby dampening the immune response (nih.gov, 1.2.5). This pathway is a major therapeutic target in oncology and immunology; CTLA-4 inhibitors like ipilimumab are used to unleash anti-tumor immunity in various cancers, while CTLA-4-Ig fusion proteins like abatacept are employed to block CD28-mediated co-stimulation in autoimmune diseases and organ transplantation (nih.gov, 1.2.1). Therapeutic manipulation of this axis requires careful management of safety concerns, most notably immune-related adverse events (irAEs) resulting from excessive immune activation or cytokine release syndrome in the case of CD28 agonists (mdpi.com, 1.4.2). The interaction between these receptors and their shared ligands forms a rheostat-like mechanism that tunes the intensity of the adaptive immune response (nih.gov, 1.2.2). While CD28 promotes the production of cytokines like IL-2, CTLA-4 can actively remove ligands from the surface of antigen-presenting cells via trans-endocytosis, further limiting co-stimulation (nih.gov, 1.2.2). Clinical success with CTLA-4 blockade has revolutionized cancer immunotherapy, although it is often associated with a higher rate of toxicity compared to other checkpoint inhibitors (mdpi.com, 1.4.2). Ongoing research focuses on selective CD28 blockade to preserve CTLA-4-mediated suppression, potentially offering a more refined approach to treating autoimmunity (nih.gov, 1.2.1).

Other names

CD28CTLA-4CD152Tp44B7-1/B7-2 receptorsCytotoxic T-lymphocyte-associated antigen 4CD28/CTLA-4 axis

The CD28/CTLA-4 axis regulates T-cell activation through competitive binding to shared ligands CD80 and CD86. CD28 engagement provides essential co-stimulatory signals, while CTLA-4 acts as a high-affinity antagonist that inhibits T-cell responses and maintains self-tolerance.