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Immune response CD28 signaling

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Immune response CD28 signaling

CD 28 signaling

Induction of immune response requires T cells to receive two sets of signals fromantigen-presenting cells. The first signal is delivered via T-cell receptor complex (TCR ), while the second one proceeds via co-receptor CD28. TCR andCD28 are independent signaling units. However, Cd28 amplifies signaltriggered by TCR ligation [1].

CD28 is a T-cell surface protein activated by interacting with the B-cellactivation antigens CD80 and CD86 [2].

In response to ligand activation, CD28 binds with the regulatory subunits ofphosphatidylinositol kinase 1 ( PIK3R1A ), adaptor proteins GRB2 andGRB2-related adaptor protein ( GRAP2 ) and T cell-specific tyrosine kinaseITK [3], [4].

Lck and Fyn are critical for the CD28 co-stimulation. Thesekinases phosphorylate motifs present in the cytoplasmic tail of CD28, thus enabling it tobind p85 subunit of PI3K and GRB2 [5]. Lck andFyn also phosphorylate and consequently activate Itk and Vav-1respectively [1], [6].

CB28 binds with SLP-76 via adaptor proteins GRB2 and GRAP2. SLP-76 recruits VAV-1, linking CD28 to VAV effectors.Mechanism of Vav-1 activation upon CD28 ligation is unclear. Putatively,TCR selectively induces ZAP-70 activation, followed by phosphorylation ofthe scaffold proteins LAT and SLP-76 [7]. LAT, inturn, can bind to the SLP-76 adaptor via GRB2 and GRAP [8].

Vav-1 exerts pleiotropic effects mediated by the Rho family of guanosinetriphosphatases (GTPases). Rac1 is a target for VAV and participates inactin cytoskeletal remodeling.

Additionally, VAV-1 regulates activity of PLC-gamma 1 by facilitatingavailability of PtdIns(4,5)P2, the PLC-gamma 1 substrate via stimulationof PIP-5 kinase, a Rac1 downstream element [9].

Itk also phosphorylates and activates PLC-gamma 1 [9].

The activated PCL-gamma 1 is responsible for synthesis of second messengersDiacylglycerol ( DAG ) and Inositol 1,4,5-triphosphate ( IP 3 )by cleaving Phosphatidylinositol 4,5 bisphosphate ( PtdIns(4,5)P2 ) at the plasmamembrane. DAG activates a number of proteins, including various isoforms ofprotein kinase C (PKC). PKC-theta activates kinase IKK, whichphosphorylates serine residues on I-kappa-B proteins, thus marking them fordestruction via ubiquitination, and, thereby, enabling activation of theNF-kappa-B complex [10].

IP3 binds IP3 Receptor (IP3R ), which is localized primarily on theendoplasmic reticulum where it stimulates release of calcium from intracellular stores.Calcium-bound Calmodulin associates with and activates serine/threoninephosphatase Calcineurin. Calcineurin dephosphorylates NF-AT familyof transcription factors leading to theirs translocation to the nucleus [11].

Activated PI3K converts PtdIns(4,5)P2 into Phosphatidylinositol3,4,5-triphosphate ( PtdIns(3,4,5)P 3 ) [12]. CD28ligation stimulates generation of PtdIns(3,4,5)P 3. PtdIns(3,4,5)P3 associates with the inner face of the plasma membrane promotingrecruitment of proteins with pleckstrin homology (PH) domains, such as ITK,VAV1, and Akt [4]. Akt blocks Glycogen synthase kinase-3 (GSK-3 ), which phosphorilates NF-AT and, thereby, prevents its nucleartranslocation [13].

Additionally, CD28 activates JNK cascade via VAV-1 activation.VAV-1 activates Rac1 and CDC24, which activate JNK viaMEKK1 and MKK4/7. Activated JNK phosphorylates transcriptionfactors such as JUN, thereby activating AP1 complex, involved in regulation ofcell proliferation [14].