Immune response ICOS pathway in T-helper cell
ICOS-pathway in T-helper cell
Induction of an immune response requires that T cells receive 2 sets of signals from antigen-presenting cells. First an antigen-specific signal is delivered through T cell receptor alpha/beta (TCR alpha/beta)- CD3 complex, while the second co-stimulatory signal is provided by co-receptors, such as CD28 molecule (CD28)and the Inducible T-cell co-stimulator (ICOS) protein[1].
ICOS acts as a co-stimulatory signal for T-cell proliferation and cytokine secretion, and mediates local tissue responses to inflammatory conditions, and modulates secondary immune response by co-stimulating memory T-cell function. ICOS stimulation plays an important role in cell-cell signaling, cytoskeleton, immune responses, and regulation of cell survival. Inducible T-cell co-stimulator ligand (B7-H2) is a ligand for ICOS [2].
When TCR alpha/beta/CD3 complex is bound to the Major Histocompatibility Complex class II (MHC class II) it initiates a biochemical cascade via Lymphocyte-specific protein tyrosine kinase (Lck) and the protein called “Zeta-chain-(TCR)-associated protein kinase 70kDa,”(ZAP70). Two known substrates of ZAP70 are the “adapter molecule Linker for activation of T cells,” (LAT) and the “Lymphocyte cytosolic protein 2,” (Slp76). Phosphorylation of tyrosine residues on LAT and Slp76 results in recruitment of a number of other proteins involved in activation of different signaling cascades. The phosphorylated adaptor LAT binds and activates the protein named “Phospholipase C, gamma 1,” (PLC-gamma 1) [3]. The activated PLC-gamma 1 is responsible for production of the second messengers diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3) from cleavage of phospha-tidylinositol 4,5-bis-phosphate (PtdIns(4,5)P2) at the plasma membrane. IP3 and DAG are second messengers that regulate various processes, such as activation of the “Nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2” (NfATC2) protein and the “Nuclear factor of kappa light polypeptide gene enhancer in B-cells” (Nf-kB), proten, rpectively.
DAG activates the protein ”Protein Kinase C-theta,” (PKC-theta). PKC-theta activates the protein ”Inhibitor of kappa light polypeptide gene enhancer in B-cells,kinase beta,” (IKK beta), which phosphorylates the protein “Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor,” (I-kB) thereby allowing activation of the NF-kB complex. IP3 induces release of Ca(2+) from the endoplasmic reticulum. Calcium-bound Calmodulin 2 (Calmodulin) associates with and activates the protein “Protein phosphatase 3 (formerly 2B), catalytic subunits –also called Calcineurin A (catalytic). Calcineurin A (catalytic) dephosphorylates the NfATC2 family of transcription factors leading to their translocation into the nucleus [4].
CD28 is stimulated by binding of the B-cell-specific cell-surface receptors CD86 molecule (CD86) and CD80 molecule (CD80). CD28 enhances T-cell functions that are essential for effective antigen-specific immune response [5]. In response to activation by the ligands, CD28 can bind to various proteins including, the protein “Phosphatidylinositol 3-kinase, regulatory subunit,” (PI3K reg class IA), and the adaptor proteins, “Growth factor receptor-bound protein 2,” (Grb2), and “T-cell-specific IL2-inducible T-cell kinase,” (ITK). ITK participates in the phosphorylation of LAT and in the activation of PCL-gamma 1 [6], [7].
Slp76 and Grb2 recruit the protein “Vav-1-guanine-nucleotide-exchange factor,” (VAV-1), which activates a protein called the “small GTPases Ras-related C3 botulinum toxin substrate 1,”(Rac1) and the protein “Cell division Cycle 42,” (CDC42). These proteins are involved in the regulation of cytoskeleton structure and remodeling [8].
T-cell receptor protein itself can not bind and activate the protein phosphatidylinositol kinase. This role is played by the protein “T cell receptor associated transmembrane adaptor 1.” (TRIM), which is a novel integral component of the TCR alpha/beta/CD3 complex co-stimulator protein [9]. Additionally, the proteins CD28 and ICOS recruit and activate phosphatidylinositol kinase.
TRIM, CD28, and ICOS bind to PI3K reg class IA and recruit it to the membrane thereby activating kinase activity. Active Phosphatidylinositol 3-kinase (catalytical subunit PI3K cat class IA) converts phosphatidylinositol 4,5-biphosphate (PtdIns(4,5)P2) to phosphatidylinositol3,4,5-triphosphate (PtdIns(3,4,5)P3) [10].
Another phosphatidylinositol kinase isoform, Phosphoinositide-3-kinase, regulatory subunit 5, (PI3K reg class IB (p101) also called Phosphoinositide-3-kinase, catalytic, gamma polypeptide (PI3K cat class IB (p110-gamma), is stimulated by the signal from a GPCR via G-protein beta/gamma. PtdIns(3,4,5)P3 is a second messenger and modulates the activity of v-akt murine thymoma viral oncogene homolog (AKT(PKB)and 3-phosphoinositide dependent protein kinase-1 (PDK(PDPK1) involved in cell survival processes [7].
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