Pathway maps

Immune response_ICOS pathway in T-helper cell
Immune response_ICOS pathway in T-helper cell

Object List (links open in MetaCore):

CD28, AKT(PKB), Rac1, TRIM, ITK, PtdIns(3,4,5)P3, IP3, Calmodulin, B7-H2, PI3K reg class IA, NF-AT1(NFATC2), LAT, BAD, ZAP70, G-protein alpha-15,, NF-kB, TCR alpha/beta, VAV-1, IKK-beta, I-kB, PDK (PDPK1), ICOS, <endoplasmic reticulum lumen> Ca('2+) = <cytosol> Ca('2+), Calcineurin A (catalytic), DAG, CDC42, CD3, Slp76, Ca(2+) cytosol,, PKC-theta, G-protein beta/gamma, GRB2, Lck, PLC-gamma 1, CD80, PI3K reg class IB (p101), PtdIns(4,5)P2, IP3 receptor, CD86, GAB2, Ca(2+) endoplasmic reticulum lumen, PI3K cat class IA, MHC class II, PI3K cat class IB (p110-gamma)


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 ( B7-H2 ) 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].


  1. McAdam AJ, Greenwald RJ, Levin MA, Chernova T, Malenkovich N, Ling V, Freeman GJ, Sharpe AH
    ICOS is critical for CD40-mediated antibody class switching. Nature 2001 Jan 4;409(6816):102-5
  2. Rudd CE, Schneider H
    Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling. Nature reviews. Immunology. 2003 Jul;3(7):544-56
  3. Lin J, Weiss A
    T cell receptor signalling. Journal of cell science 2001 Jan;114(Pt 2):243-4
  4. Rusnak F, Mertz P
    Calcineurin: form and function. Physiological reviews 2000 Oct;80(4):1483-521
  5. Pollard KM, Arnush M, Hultman P, Kono DH
    Costimulation requirements of induced murine systemic autoimmune disease. Journal of immunology (Baltimore, Md. : 1950) 2004 Nov 1;173(9):5880-7
  6. Marengere LE, Okkenhaug K, Clavreul A, Couez D, Gibson S, Mills GB, Mak TW, Rottapel R
    The SH3 domain of Itk/Emt binds to proline-rich sequences in the cytoplasmic domain of the T cell costimulatory receptor CD28. Journal of immunology (Baltimore, Md. : 1950) 1997 Oct 1;159(7):3220-9
  7. Rudd CE, Raab M
    Independent CD28 signaling via VAV and SLP-76: a model for in trans costimulation. Immunological reviews 2003 Apr;192:32-41
  8. Raab M, Pfister S, Rudd CE
    CD28 signaling via VAV/SLP-76 adaptors: regulation of cytokine transcription independent of TCR ligation. Immunity 2001 Dec;15(6):921-33
  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
  10. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD
    Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annual review of cell and developmental biology 2001;17:615-75