| CTLA‑4 (CD152) is an immunoglobulin superfamily receptor expressed on activated conventional T cells and at high, constitutive levels on FoxP3⁺ regulatory T cells, where it functions as a dominant negative checkpoint that constrains co‑stimulation and maintains peripheral tolerance by counterbalancing CD28 signals. The extracellular domain shares structural homology with CD28 and binds the same ligands, CD80 and CD86, but with higher affinity and avidity, allowing CTLA‑4 to outcompete CD28 for limited B7 molecules at the immunological synapse and to remove them from antigen‑presenting cells by trans‑endocytosis, which reduces B7 density and blunts further T‑cell co‑stimulation. The short cytoplasmic tail lacks intrinsic enzymatic activity but contains tyrosine‑based motifs and a lysine‑rich region that recruit signaling and trafficking partners: phosphorylation‑dependent association with the clathrin adaptor AP‑2 and other endocytic machinery keeps most CTLA‑4 in intracellular vesicles, while ligand engagement drives its rapid accumulation at the synapse, and interaction with phosphatases such as SHP‑2 and PP2A attenuates proximal TCR and CD28 signaling by dephosphorylating key components of the activation cascade. Regulatory T cells use CTLA‑4 to impose extrinsic suppression on neighboring T cells by depleting CD80/CD86 from dendritic cells and altering their cytokine profile, whereas effector T cells depend on induced CTLA‑4 to terminate their own expansion after antigen encounter, and germline or functional loss of CTLA4 in mice and humans leads to unrestrained CD28‑driven activation, severe lymphoproliferation, multiorgan infiltration, and early lethality or systemic immune dysregulation syndromes, establishing CTLA‑4 as a non‑redundant brake on self‑reactive T cells. Genetic variation at the CTLA4 locus associates with multiple autoimmune diseases, including type 1 diabetes, autoimmune thyroid diseases, celiac disease, and systemic lupus erythematosus, consistent with modest reductions in CTLA‑4 expression or function tipping the balance toward autoreactivity. In the tumor microenvironment, CTLA‑4 on effector and regulatory T cells contributes to T‑cell dysfunction and tolerance to tumor antigens, and antibody‑mediated CTLA‑4 blockade restores costimulation, expands tumor‑reactive clones, and depletes intratumoral Tregs, leading to durable tumor regressions in a subset of patients but also immune‑related adverse events that mirror the pathway’s central role in tolerance. |
