Immune response - NFAT in immune response

NFAT in immune response

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

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

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

One of the known substrates of ZAP-70 is the adapter molecule Linker for activation of T cells (LAT). The phosphorylation of tyrosine residues on LAT results in recruitment and activation Phospholipase C, gamma 1 (PLC-gamma 1). The other target for ZAP-70 is the adaptor protein Lymphocyte cytosolic protein 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 [5].

CD28, in response to ligation by antigens CD80 and CD86, recruits T cell-specific tyrosine kinase IL2-inducible T-cell kinase (ITK), which phosphorylates and activates PCL-gamma-1 [6].

The B-Cell antigen Receptor (BCR) plays a critical role in the activation of B lymphocytes and regulation of immune response. The BCR is composed of membrane immunoglobulin (IgM) molecules and associated with CD79a molecule, immunoglobulin-associated alpha - CD79b molecule, immunoglobulin-associated beta heterodimers (CD79 complex) [7]. The IgM subunits bind antigen and cause receptor aggregation, while the CD79 complex transduces signals to the cell interior. Receptor engagement leads to the activation of intracellular protein tyrosine kinases Syk and Lyn, which phosphorylate and activate phospholipases 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 the surface 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 tyrosine kinase (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 the production of the second messengers diacylglycerol (DAG)and inositol 1,4,5-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), which is localized primarily on the endoplasmic reticulum and stimulates the release of calcium from intracellular stores. Calcium-bound Calmodulin 2 (Calmodulin) associates with and activates Protein phosphatase 3, catalytic subunit (Calcineurin A (catalytic)). Calcineurin A (catalytic) dephosphorylates NF-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 kinase IKK-cat complex by phosphorylation Inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta (IKK-beta). Active IKK-cat phosphorylates of serine residues on the Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor (I-kB) proteins marks them for destruction via the ubiquitination pathway, thereby allowing activation of the Nuclear factor of kappa light polypeptide 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 (PI3K cat class IA). PI3K cat class IA converts phosphatidylinositol 4,5-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 inner bilayer of the plasma membrane promoting the recruitment of proteins with pleckstrin homology (PH) domains, such as the V-akt murine thymoma viral oncogene homolog 1 (AKT(PKB)). Activation of AKT(PKB) participates in stimulation NF-kB via Conserved helix-loop-helix ubiquitous kinase (IKK-alpha) activation [5]. Moreover, stimulated AKT(PKB) blocks the action of Glycogen synthase kinase-alpha/beta (GSK3alpha/beta), which phosphorylates Nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 4 (NF-AT3(NFATC4)), preventing its nuclear translocation [14].

References:

1. Porter CM, Havens MA, Clipstone NA
   Identification of amino acid residues and protein kinases involved in the regulation of NFATc subcellular localization. The Journal of biological chemistry 2000 Feb 4;275(5):3543-51
2. Lanier LL, O'Fallon S, Somoza C, Phillips JH, Linsley PS, Okumura K, Ito D, Azuma M
   CD80 (B7) and CD86 (B70) provide similar costimulatory signals for T cell proliferation, cytokine production, and generation of CTL. Journal of immunology (Baltimore, Md. : 1950) 1995 Jan 1;154(1):97-105
3. Slavik JM, Hutchcroft JE, Bierer BE
   CD80 and CD86 are not equivalent in their ability to induce the tyrosine phosphorylation of CD28. The Journal of biological chemistry 1999 Jan 29;274(5):3116-24
4. Nel AE
   T-cell activation through the antigen receptor. Part 1: signaling components, signaling pathways, and signal integration at the T-cell antigen receptor synapse. The Journal of allergy and clinical immunology 2002 May;109(5):758-70
5. Lin J, Weiss A
   T cell receptor signalling. Journal of cell science 2001 Jan;114(Pt 2):243-4
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. Geisberger R, Crameri R, Achatz G
   Models of signal transduction through the B-cell antigen receptor. Immunology 2003 Dec;110(4):401-10
8. Pao LI, Cambier JC
   Syk, but not Lyn, recruitment to B cell antigen receptor and activation following stimulation of CD45- B cells. Journal of immunology (Baltimore, Md. : 1950) 1997 Mar 15;158(6):2663-9
9. Mohamed AJ, Nore BF, Christensson B, Smith CI
   Signalling of Bruton's tyrosine kinase, Btk. Scandinavian journal of immunology 1999 Feb;49(2):113-8
10. Eiseman E, Bolen JB
    Engagement of the high-affinity IgE receptor activates src protein-related tyrosine kinases. Nature 1992 Jan 2;355(6355):78-80
11. Kihara H, Siraganian RP
    Src homology 2 domains of Syk and Lyn bind to tyrosine-phosphorylated subunits of the high affinity IgE receptor. The Journal of biological chemistry 1994 Sep 2;269(35):22427-32
12. Hogan PG, Chen L, Nardone J, Rao A
    Transcriptional regulation by calcium, calcineurin, and NFAT. Genes & development 2003 Sep 15;17(18):2205-32
13. Tan SL, Parker PJ
    Emerging and diverse roles of protein kinase C in immune cell signalling. The Biochemical journal 2003 Dec 15;376(Pt 3):545-52
14. Graef IA, Mermelstein PG, Stankunas K, Neilson JR, Deisseroth K, Tsien RW, Crabtree GR
    L-type calcium channels and GSK-3 regulate the activity of NF-ATc4 in hippocampal neurons. Nature 1999 Oct 14;401(6754):703-8