Immune response - T cell receptor signaling pathway

T cell receptor signaling pathway

T cell receptors (TCR) play a key role in functioning of T cells and formation of the immunological synapse. It provides connection between T cell and the antigen-presenting cell (APC) [1]. TCRs are composed of ligand-binding subunits, the alpha and beta chains, and signaling subunits, namely the CD3 epsilon, gamma, delta and zeta chains. Small population of T cells contains TCRs that consist of gamma and delta chains instead alpha and beta [2].

The coordinated activation of T cells by foreign antigens leads to a clonal expansion, differentiation, cytotoxic killing, or induction of programmed cell death. The T-cell activation is initiated by the TCR.

The physiologic ligand for the TCR alpha/beta is a foreign peptide bound to the Major histocompatibility complex, class II (MHC class II) expressed on the APC [2].

CD4 acts as a cellular adhesion molecule, binds MHC class II molecules, and stabilizes the interaction of T cells and APCs [3].

TCR alpha/beta ligation leads to the activation of the Src family kinases Lck and Fyn. How exactly these Src kinases are activated is not clear. However, it was shown that tyrosine phosphatase CD45 participates in the formation of multimeric complexes with the CD4 receptor that is physically associated with Lck [2]. Additionally, CD45 dephosphorylates and activates Lck and Fyn [4]. Activated Lck and Fyn phosphorylate CD3 chains, and promote the recruitment and subsequent activation of another tyrosine kinase ZAP-70 [5].

ZAP-70 phosphorylates adaptor LAT that in turn binds to Phospholipase C gamma 1 (PCL-gamma 1) and activates it. Activated PCL-gamma 1 is responsible for the production of the second messengers Diacylglycerol (DAG) and Inositol 1,4,5-triphosphate (IP3) by cleaving Phosphatidylinositol 4,5 bisphosphate (PtdIns(4,5) P2) in the plasma membrane.

DAG activates a number of proteins, including various isoforms of protein kinase C (PKC). Some of them (PKC-theta in particular) participate in the Nuclear factor NF-kappa-B (NF-kB) pathway [5].

Another second messenger, IP3, stimulates efflux of Ca2+ from endoplasmic reticulum to the cytosol [6]. Elevated Ca2+ levels activate the protein phosphatase Calcineurin. Calcineurin dephosphorylates Nuclear factors of activated T-cells NF-AT1(NFATC2), NF-AT2(NFATC1), NF-AT3(NFATC4), and NF-AT4(NFATC3), which allow them to enter the nucleus where they cooperates with other transcription factors and bind to promoter regions of specific genes [7].

Ca2+ and DAG also activate Calcium and diacylglycerol-regulated guanine nucleotide exchange factor II (CalDAG-GEFII) that stimulates H-Ras [8]. Moreover, phosphorylated LAT binds GRB2. The latter activates Son of sevenless homolog 1 and 2 (SOS)/ v-Ha-Ras Harvey rat sarcoma viral oncogene homolog (H-Ras)/ v-Raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1)/ Mitogen-activated protein kinase kinase 1 and 2 (MEK1 and MEK2)/ Mitogen-activated protein kinases 1 and 3 (ERK1/2) signaling. ERK1/2 kinases phosphorylate transcription factor ELK1 member of ETS oncogene family (Elk-1) and transcription factors of the Activator protein 1 (AP-1) family, such as c-Fos. Thus, transcription factors AP-1, NF-kB and NFAT participate in the immune response of the organism [5].

References:

1. Bromley SK, Burack WR, Johnson KG, Somersalo K, Sims TN, Sumen C, Davis MM, Shaw AS, Allen PM, Dustin ML
   The immunological synapse. Annual review of immunology 2001;19:375-96
2. 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
3. Krummel MF, Sjaastad MD, Wulfing C, Davis MM
   Differential clustering of CD4 and CD3zeta during T cell recognition. Science (New York, N.Y.) 2000 Aug 25;289(5483):1349-52
4. Li R, Wong N, Jabali MD, Johnson P
   CD44-initiated cell spreading induces Pyk2 phosphorylation, is mediated by Src family kinases, and is negatively regulated by CD45. The Journal of biological chemistry 2001 Aug 3;276(31):28767-73
5. Lin J, Weiss A
   T cell receptor signalling. Journal of cell science 2001 Jan;114(Pt 2):243-4
6. Katan M
   The control of inositol lipid hydrolysis. Cancer surveys 1996;27:199-211
7. Rusnak F, Mertz P
   Calcineurin: form and function. Physiological reviews 2000 Oct;80(4):1483-521
8. Toki S, Kawasaki H, Tashiro N, Housman DE, Graybiel AM
   Guanine nucleotide exchange factors CalDAG-GEFI and CalDAG-GEFII are colocalized in striatal projection neurons. The Journal of comparative neurology 2001 Sep 3;437(4):398-407