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 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 Inducible T-cell co-stimulator (ICOS) [1].

ICOS acts as a costimulatory signal for T-cell proliferation and cytokine secretion, and mediates local tissue responses to inflammatory conditions, 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. Iinducible T-cell co-stimulator ligand (ICOS-L) is a ligand for ICOS [2].

TCR alpha/beta/CD3 complex bound to Major histocompatibility complex class II (MHC class II) initiates a biochemical cascade via Lymphocyte-specific protein tyrosine kinase (Lck) and Zeta-chain (TCR) associated protein kinase 70kDa (ZAP70). Two known substrates of ZAP70 are adapter molecules Linker for activation of T cells (LAT) and 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 Phospholipase C, gamma 1 (PCL-gamma 1) [3]. The activated PCL-gamma 1 is responsible for production of second messengers diacylglycerol (DAG) and inositol 1, 4, 5-triphosphate (IP3) from cleavage of phospha-tidylinositol 4, 5 bisphosphate (PtdIns(4,5)P2) at plasma membrane. IP3 and DAG are second messengers that regulate various processes, such as activation of Nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 (NF-AT1(NFATC2)) and Nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-kB), respectively.

DAG activates Protein kinaseC-theta (PKC- theta). PKC- theta activates Inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta (IKK beta), which phosphorylates Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor (I-kB) thereby allowing activation of NF-kB complex. IP3 induces release of Ca('2+) from endoplasmatic reticulum. Calcium-bound Calmodulin 2 (Calmodulin) associates with and activates Protein phosphatase 3 (formerly 2B), catalytic subunits (Calcineurin A (catalytic)). Calcineurin A (catalytic) dephosphorylates NF-AT1(NFATC2) family of transcription factors leading to theirs translocation into the nucleus [4].

CD28 is stimulated by binding of 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 the Phosphatidylinositol 3-kinase, regulatory subunit (PI3K reg class IA), adaptor proteins Growth factor receptor-bound protein 2 (GRB2), and T cell-specific IL2-inducible T-cell kinase (ITK). ITK participates in phosphorylation of LAT and in the activation of PCL-gamma 1 [6], [7].

Slp76 and GRB2 recruit Vav 1 guanine nucleotide exchange factor (VAV-1), which activates small GTPases Ras-related C3 botulinum toxin substrate 1 (Rac1) and Cell division cycle 42 (CDC42) involved in regulation of cytoskeleton structure and remodeling [8].

T-cell receptor itself can't bind and activate phosphatidylinositol kinase. This role is played by T cell receptor associated transmembrane adaptor 1 (TRIM), which is a novel integral component of TCR alpha/beta/CD3 complex co-stimulators [9]. Additionally, 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 phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) [10]. Another phosphatidylinositol kinase isoform, Phosphoinositide-3-kinase, regulatory subunit 5 (PI3K reg class IB (p101)) - Phosphoinositide-3-kinase, catalytic, gamma polypeptide (PI3K cat class IB (p110-gamma)), is stimulated by the signal from 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].

References:

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   T cell receptor signalling. Journal of cell science 2001 Jan;114(Pt 2):243-4
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   Calcineurin: form and function. Physiological reviews 2000 Oct;80(4):1483-521
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9. Kirchgessner H, Dietrich J, Scherer J, Isomaki P, Korinek V, Hilgert I, Bruyns E, Leo A, Cope AP, Schraven B
   The transmembrane adaptor protein TRIM regulates T cell receptor (TCR) expression and TCR-mediated signaling via an association with the TCR zeta chain. The Journal of experimental medicine 2001 Jun 4;193(11):1269-84
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