CTLA4

CTLA4 (cytotoxic T-lymphocyte-associated protein 4, CD152) encodes a type I transmembrane inhibitory co-receptor of the immunoglobulin superfamily. CTLA4 contains an extracellular Ig-like V-type domain that binds B7 family ligands CD80 (B7-1) and CD86 (B7-2) on antigen-presenting cells with higher avidity than the stimulatory co-receptor CD28, thereby competitively inhibiting T cell co-stimulation at the priming phase (PMID:11279501, PMID:11279502). CTLA4 functions as a disulfide-linked homodimer. Its surface expression is tightly regulated by constitutive clathrin-mediated endocytosis and recycling; at steady state it resides largely in intracellular vesicles (Golgi, endosomes, perinuclear region), with surface expression induced upon T cell activation. CTLA4 is constitutively expressed on FoxP3+ regulatory T cells (Tregs), where it mediates suppressive function including trans-endocytosis of CD80/CD86 from dendritic cells (CTLA4-deep-research-falcon.md). The cytoplasmic tail contains a YVKM motif whose phosphorylation at Tyr-201 by TXK and JAK2 regulates AP-2 binding and endocytic trafficking. Haploinsufficiency causes IDAIL (immune dysregulation with autoimmunity, immunodeficiency, and lymphoproliferation), and common variants confer susceptibility to type 1 diabetes, Graves disease, celiac disease, and SLE. Anti-CTLA4 antibodies (ipilimumab, tremelimumab) are used in cancer immunotherapy; CTLA4-Ig fusions (abatacept, belatacept) are used to treat autoimmunity and prevent transplant rejection.

Disorders

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