CTLA4 Signaling in Cytotoxic T Lymphocytes

CTLA4 is an essential negative regulator of T-cell activation. Costimulation involves an integration of activating signals (CD28) and inhibitory signals (CTLA4) with TCR / MHC signals to determine the outcome of a T-cell's encounter with antigen on a presenting cell. Expression of CTLA4 is dependent both on TCR stimulation by antigens and on CD28 engagement with the activating proteins CD80 and CD86. At the cell membrane, CTLA4 undergoes dimerization, and each CTLA4 dimer can bind two independent CD80/CD86 homodimers, forming a linear zipper-like structure between CD80/CD86 and CTLA-4 homodimers. CTLA4 binds CD80/86 with 500 to 2500 times greater avidity than does CD28, competitively reducing binding with activating receptor CD28. Activated CTLA4 binds to PI3K, the tyrosine phosphatases SHP1 and SHP2, and the serine/threonine phosphatase PP2A. SHP1 and SHP2 dephosphorylate TCR signaling proteins, whereas PP2A targets phosphoserine/threonine residues, inhibiting AKT. Binding of CTLA4 to PI3K suggests that the co-receptor could generate positive signals in common with CD28. But in the context of additional negative-signaling events, such as PP2A, SHP1 and SHP2, interference with T-cell activation would predominate.The activation of T-cells by antigen-MHC-I complex carried on presenting cells initiates a cascade of events, the first of which is phosphorylation of the PTKs belonging to the Src and SYK / ZAP70 families. Initiation of T-cell activation is mediated by phosphorylation of the ITAMs on the TCR-CD3 complex by Lck, and Fyn. The phosphorylated ITAMs then bind the SH2 domains of ZAP70 / SYK. This in turn results in phosphorylation and activation of ZAP70 and SYK, which amplify signals from the TCR through the activation of the adaptor proteins LAT, SLP76, GADS, TRIM and enzymatic effectors such as PLC-γ1 in order to trigger an immune response. Signaling through CD28 is the essential second signal for T-cell activation, and activates PRKCQ and PI3K, and promotes cytokine IL-2 production and entry into the cell cycle, T-cell survival, T-helper-cell differentiation and immunoglobulin isotype switching. CTLA4 inhibits CD28, (possibly directly, but certainly through competition for CD80 and CD86 at the immunological synapse), particularly its recruitment of PRKCQ.CTLA4 occurs mostly in intracellular vesicles, with very little at the cell surface. CTLA4 is unique in binding to the clathrin adaptor complexes, such as AP2 and AP1, through its nonphosphorylated Tyr-Val-Lys-Met motif. AP2 regulates endocytosis of CTLA4, whereas AP1 controls the amount of intracellular CTLA4 via lysosomal degradation. T-cell activation prompts more CTLA4 expression, presumably as a homeostatic mechanism, but regulation of cell surface trafficking remains unclear. CTLA4 may also act trans-cellularly to induce endocytosis of liganded CD80/CD86 receptors on antigen presenting cells.CTLA4 regulates signal transduction which leads to differentiation into regulatory T-cells or alters cytokine production. CTLA4 is involved in the dysregulation of tolerance in autoimmune diseases such as diabetes and thyroiditis as well as a predisposition toward spontaneous abortion. Knockout animals die in infancy from uncontrolled T-cell activation. A SNP in exon1 of CTLA4 is associated with susceptibility to several autoimmune diseases, including multiple sclerosis. Anti-CTLA4 agents are now commonly used as immune stimulants, similar to or along with anti-PD1/PD-L1, especially in cancer immunotherapies to counteract tumor-expressed immune suppressors. (32007707, 20870175, 21904389, 30219287, 31758533) (Upgraded 04/2022)