Introduction
CTLA4 Signaling Pathway
Introduction
CTLA4, also known as CD152, is a member of the immunoglobulin superfamily. CTLA4 is a T cell surface transmembrane protein encoded by the CTLA4 gene and is expressed mainly on the surface of activated CD4+ and CD8+ T lymphocytes as well as activated B lymphocytes. The human CTLA4 gene is located in the long arm 33 band of chromosome 2 and contains four exons encoding the leader sequence, the ligand binding region, the transmembrane region, and the cytoplasmic tail region, respectively. CTLA4 has two subtypes: full-length CTLA4 (flCTLA4) encoded by four exons and soluble CTLA4 (sCTLA4) encoded by three exons other than the transmembrane region. sCTLA4 is derived from an alternative splicing that results in the loss of a cysteine residue and is a soluble monomeric protein present in serum. Activated T cells have low expression of sCTLA4 protein and high expression of flCTLA4 protein.
Figure 1. CTLA4 functions as a dual regulator of T cell activation
CTLA4 plays an important role in the development of autoimmune diseases. The levels of soluble CTLA4 in serum of patients with various autoimmune diseases such as Graves' disease (GD), systemic lupus erythematosus (SLE), and celiac disease (CD) is higher than the healthy control group, but the biological significance of this high expression has not been fully elucidated. Simone et al. found that CTLA4 regulates disease progression by regulating the balance of anti-inflammatory/pro-inflammatory cytokines during autoimmune responses.
Expression of CTLA4 and Its Effect on Immune Response
The function and mechanism of action of CTLA4 have been studied for many years, but no conclusion has yet been established. It is generally accepted that CTLA4 plays a negative regulatory role in the activation of T cells, thereby maintaining the activation balance of T cells. Among the co-stimulatory signals necessary for T cell activation, B7/CD28 signaling plays an important role. CD28 molecules are constitutively expressed on the surface of T cells and can bind to the surface of APC when homologous APC/T cells interact. B7-1 (CD80) and B7-2 (CD86), which transmit signals through CD28, promote T cell activation, proliferation, and cytokine production. Another receptor for the B7 molecule is CTLA4. In contrast to CD28, CTLA4 is not constitutively expressed in T cells and is only up-regulated when T cells are over-activated. There is increasing evidence that CTLA4-positive cells modify the phenotype of APCs, thereby modulating the initiation of naive T cells. It should be noted that CTLA4 can down-regulate the expression of costimulatory ligands on APC by transendocytosis, thereby inhibiting the proliferation and activation of T cells.
Introduction
CTLA4, also known as CD152, is a member of the immunoglobulin superfamily. CTLA4 is a T cell surface transmembrane protein encoded by the CTLA4 gene and is expressed mainly on the surface of activated CD4+ and CD8+ T lymphocytes as well as activated B lymphocytes. The human CTLA4 gene is located in the long arm 33 band of chromosome 2 and contains four exons encoding the leader sequence, the ligand binding region, the transmembrane region, and the cytoplasmic tail region, respectively. CTLA4 has two subtypes: full-length CTLA4 (flCTLA4) encoded by four exons and soluble CTLA4 (sCTLA4) encoded by three exons other than the transmembrane region. sCTLA4 is derived from an alternative splicing that results in the loss of a cysteine residue and is a soluble monomeric protein present in serum. Activated T cells have low expression of sCTLA4 protein and high expression of flCTLA4 protein.
Figure 1. CTLA4 functions as a dual regulator of T cell activation
CTLA4 plays an important role in the development of autoimmune diseases. The levels of soluble CTLA4 in serum of patients with various autoimmune diseases such as Graves' disease (GD), systemic lupus erythematosus (SLE), and celiac disease (CD) is higher than the healthy control group, but the biological significance of this high expression has not been fully elucidated. Simone et al. found that CTLA4 regulates disease progression by regulating the balance of anti-inflammatory/pro-inflammatory cytokines during autoimmune responses.
Expression of CTLA4 and Its Effect on Immune Response
The function and mechanism of action of CTLA4 have been studied for many years, but no conclusion has yet been established. It is generally accepted that CTLA4 plays a negative regulatory role in the activation of T cells, thereby maintaining the activation balance of T cells. Among the co-stimulatory signals necessary for T cell activation, B7/CD28 signaling plays an important role. CD28 molecules are constitutively expressed on the surface of T cells and can bind to the surface of APC when homologous APC/T cells interact. B7-1 (CD80) and B7-2 (CD86), which transmit signals through CD28, promote T cell activation, proliferation, and cytokine production. Another receptor for the B7 molecule is CTLA4. In contrast to CD28, CTLA4 is not constitutively expressed in T cells and is only up-regulated when T cells are over-activated. There is increasing evidence that CTLA4-positive cells modify the phenotype of APCs, thereby modulating the initiation of naive T cells. It should be noted that CTLA4 can down-regulate the expression of costimulatory ligands on APC by transendocytosis, thereby inhibiting the proliferation and activation of T cells.
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