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Immune response NFAT in immune response


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Immune response NFAT in immune response

NFAT in immune response

The Nuclear factors of activated T cells ( NFAT ) transcription factors familyplays a pivotal role in initiation and coordination of the immune response in a differenttypes of immune system cells, including T- and B cells, mast cells, basophiles andnatural killer cells [1].

The induction of an immune response requires that T cells receive 2 sets of signalsfrom antigen-presenting cells. The first signal is delivered through the T-cell receptorcomplex, while the second is provided by the B-cell activation antigens CD80 molecule (CD80 ) and CD86 molecule ( CD86 ), by interaction with the T-cell surfacemolecules, CD28 molecule ( CD28 ) [2], [3], [4].

The T-cell receptor complex (TCR/CD3 complex) is comprised of a ligand-binding T-cellreceptor alpha/beta heterodimer complexes ( TCR alpha/beta ) and signalingsubunits CD3 molecules ( CD3 ). The physiologic ligand for the TCRalpha/beta is foreign peptide bound to the Major histocompatibility complex, class II( MHC class II ) expressed on antigen-presenting cells [4]. Uponactivation of the TCR, the Lymphocyte-specific protein tyrosine kinase ( Lck )becomes activated. The activated Lck phosphorylates the CD247 molecule ( CD3zeta ), which promotes the recruitment and subsequent activation of anotherZeta-chain (TCR) associated protein kinase 70kDa ( ZAP-70 ) [5].

One of the known substrates of ZAP-70 is the adapter molecule Linker foractivation of T cells (LAT) . The phosphorylation of tyrosine residues onLAT results in recruitment and activation Phospholipase C, gamma 1 ( PLC-gamma1 ). The other target for ZAP-70 is the adaptor protein Lymphocyte cytosolicprotein 2 ( SLP76 ), which recruits Vav 1 guanine nucleotide exchange factor (VAV-1 ). VAV-1 activates Ras-related C3 botulinum toxin substrate 1 (Rac1 ) that participates in actin cytoskeletal remodeling [6].

The B-Cell antigen Receptor ( BCR ) plays a critical role in the activation of Blymphocytes and regulation of immune response. The BCR is composed of membraneimmunoglobulin ( IgM ) molecules and associated with CD79a molecule,immunoglobulin-associated alpha - CD79b molecule, immunoglobulin-associated betaheterodimers ( CD79 complex ) [7]. The IgM subunits bindantigen and cause receptor aggregation, while the CD79 complex transduces signalsto the cell interior. Receptor engagement leads to the activation of intracellularprotein tyrosine kinases Syk and Lyn, which phosphorylate and activatephospholipases PLC-gamma-1 and -2, and Bruton tyrosine kinase ( BTK), respectively. BTK also activates both PLC-gamma isoforms [8], [9].

The high-affinity IgE receptor ( Fc epsilon RI ), which is expressed on thesurface of mast cells and basophils, has a central role in immediate allergic responses[10]. The aggregation of the high affinity IgE receptor ( Fc epsilon RI) to the antigen results in activation of the protein tyrosine kinases Spleen tyrosinekinase ( Syk ) and v-yes-1 Yamaguchi sarcoma viral related oncogene homolog (Lyn ), leading to PLC-gamma 1 and 2 activation [11].

Activated PCL-gamma in the all types of these cells is responsible for theproduction of the second messengers diacylglycerol ( DAG )and inositol1,4,5-triphosphate ( IP3 ) by cleaving phospha-tidylinositol 4,5 bisphosphate (PtdIns(4,5)P2 ) at the plasma membrane.

IP3 binds Inositol 1,4,5-triphosphate receptor ( IP3 Receptor ), whichis localized primarily on the endoplasmic reticulum and stimulates the release of calciumfrom intracellular stores. Calcium-bound Calmodulin 2 ( Calmodulin ) associateswith and activates Protein phosphatase 3, catalytic subunit ( Calcineurin A(catalytic) ). Calcineurin A (catalytic) dephosphorylatesNF-AT1(NFATC2) leading to theirs translocation to the nucleus [12].

DAG activates various isoforms of protein kinase C, including Protein kinase C,theta ( PKC-theta ). It was shown, PKC-theta activates kinaseIKK-cat complex by phosphorylation Inhibitor of kappa light polypeptide geneenhancer in B-cells, kinase beta ( IKK-beta ). Active IKK-catphosphorylates of serine residues on the Nuclear factor of kappa light polypeptide geneenhancer in B-cells inhibitor ( I-kB ) proteins marks them for destruction via theubiquitination pathway, thereby allowing activation of the Nuclear factor of kappa lightpolypeptide gene enhancer in B-cells ( NF-kB ) [13].

In addition, CD28 recruits Phosphoinositide-3-kinase, regulatory subunit (PI3K reg class IA ) that stimulates Phosphoinositide-3-kinase, catalytic ( PI3Kcat class IA ). PI3K cat class IA converts phosphatidylinositol4,5-biphosphate ( PtdIns(4,5)P2 ) to phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3 ). PtdIns(3,4,5)P3 in turn, associates with the innerbilayer of the plasma membrane promoting the recruitment of proteins with pleckstrinhomology (PH) domains, such as the V-akt murine thymoma viral oncogene homolog 1 (AKT(PKB) ). Activation of AKT(PKB) participates in stimulation NF-kBvia Conserved helix-loop-helix ubiquitous kinase ( IKK-alpha ) activation [5]. Moreover, stimulated AKT(PKB) blocks the action of Glycogen synthasekinase-alpha/beta ( GSK3alpha/beta ), which phosphorylates Nuclear factor ofactivated T-cells, cytoplasmic, calcineurin-dependent 4 ( NF-AT3(NFATC4) ),preventing its nuclear translocation [14].