T cell receptor

Rice University

Department of Biochemistry and Cell Biology

Signal transduction through the
T cell receptor

The T cell receptor (TCR) is a complex of integral membrane proteins that participates in the activation of T cells in response to the presentation of antigen. Specific recognition and binding by the clonotype-specific a/b heterodimer leads to activation of transcription and commitment of the T cell to CD4+ or CD8+ fate. This activation involves other subunits of the receptor complex as well as other membrane-associated molecules that couple the extracellular liganding event to downstream signaling pathways such as protein phosphorylation, the release of inositol phosphates and the elevation of intracellular calcium levels. This discussion of TCR signaling focusses on the involvement of TM domains, rather than on providing a complete overview.

The intracellular portions of the CD3 g, d, e, and z subunits contain copies of a sequence motif termed ITAMs (immunoreceptor tyrosine-based activation motifs). ITAMs can serve as protein tyrosine kinase substrates and, after phosphorylation, as binding sites for SH2 domains of yet other kinases. The regulation and mechanism of the recruitment of protein kinases to the activated T cell receptor is being studied intensively; members of both the Syk family (ZAP-70) and Src family (Lck) of kinases are involved in this process.

Interactions between transmembrane domains are important for the function of the TCR. The TMs of TCR a and CD3 d appear to form an ion pair that is required for proper assembly and cell-surface expression of the TCR. Mutagenesis of the CD3 z TM shows that this domain mediates sequence-specific homodimerization as well as heteromeric interactions. Mutations to the TM domain of TCR b have been shown to abrogate signaling through certain downstream pathways without affecting receptor assembly.

Lateral associations between TM helices are also involved in transmission of signals from the activated TCR to downstream effector pathways. Activation of kinases by the phosphatase CD45 appears to be facilitated by CD45-associated protein, which binds kinases with its intracellular domain and CD45 via TM-TM contacts. Recruitment of phosphatidylinositol-3-kinase to the membrane by pp30 (T cell receptor interacting molecule, TRIM) depends on the phosphorylation of intracellular tyrosines on TRIM. While the basis for the TRIM-TCR interaction is poorly defined at present, the TM of TRIM contributes to its homodimerization.

Reviews of TCR-related subjects

"Signal transduction by the TCR for antigen"
LP Kane, J Lin and A Weiss
Curr Opin Immunol (2000) 12(3), 242-9

"T cell antigen-receptor signal transduction"
JE van Leeuwen and LE Samelson
Curr Opin Immunol (1999) 11(3), 242-8

"Antigen receptor signaling: integration of protein tyrosine kinase functions"
I Tamir and JC Cambier
Oncogene (1998) 17, 1353-64

"The next wave: protein tyrosine phosphatases enter T cell antigen receptor signalling"
T Mustelin, J Brockdorff, L Rudbeck, A Gjorloff-Wingren, S Han, X Wang, P Tailor and M Saxena
Cell Signal (1999) 11(9), 637-50

Lck
"Lck protein tyrosine kinase is a key regulator of T-cell activation and a target for signal intervention by Herpesvirus saimiri and other viral gene products"
N Isakov and B Biesinger
Eur J Biochem (2000) 267(12), 3413-21

"Molecular requirements for lineage commitment in the thymus--antibody-mediated receptor engagements reveal a central role for lck in lineage decisions"
MA Basson, U Bommhardt, PJ Mee, VL Tybulewicz and R Zamoyska
Immunol Rev (1998) 165 181-94

"Structures of Src-family tyrosine kinases"
F Sicheri and J Kuriyan
Curr Opin Struct Biol (1997) 7(6), 777-85

"Signalling by the p60c-src family of protein-tyrosine kinases"
P Kefalas, TR Brown and PM Brickell
Int J Biochem Cell Biol (1995) 27(6), 551-63

ZAP-70
"Tyrosine kinase SYK: essential functions for immunoreceptor signalling"
M Turner, E Schweighoffer, F Colucci, JP Di Santo and VL Tybulewicz
Immunol Today (2000) 21(3), 148-54

"The Syk family of protein tyrosine kinases in T-cell activation and development"
DH Chu, CT Morita and A Weiss
Immunol Rev (1998) 165(1), 167-80

"ZAP-70 and defects of T-cell receptor signaling"
ME Elder
Semin Hematol (1998) 35(4), 310-20

Cytoskeleton
"T cell activation and the cytoskeleton"
A Acuto and D Cantrell
Annu Rev Immunol (2000) 18, 165-84

"Searching for significance in TCR-cytoskeleton interactions"
S Caplan and M Baniyash
Immunol Today (2000) 21(5), 223-8

Lipid rafts
"Membrane rafts and signaling by the multichain immune recognition receptors"
C Langlet, AM Bernard, P Devrot and HT He
Curr Opin Immunol (2000) 12(3), 250-5

"The role of lipid rafts in T cell antigen receptor (TCR) signalling"
PW Janes, SC Ley, AI Magee and PS Kabouridis
Semin Immunol (2000) 12(1), 23-34

"Notch signaling in T cell development"
ML Deftos and MJ Bevan
Curr Opin Immunol (2000) 12(2), 166-72

"Molecular interactions between extracellular components of the T-cell receptor signaling complex"
KC Garcia
Immunol Rev (1999) 172, 73-85

Integrins
"Regulation of integrin function by T cell activation: points of convergence and divergence"
T Zell, WJ Kivens, SA Kellerman and Y Shimizu
Immunol Res (1999) 20(2), 127-45

"b1-integrin-mediated cell signaling in T lymphocytes"
S Iwata, Y Ohashi, K Kamiguchi and C Morimoto
J Dermatol Sci (2000) 23(2), 75-86

Adaptor proteins
"Integration of receptor-mediated signals in T cells by transmembrane adaptor proteins"
B Schraven, A Marie-Cardine, C Hubener, E Bruyns and I Ding
Immunol Today (1999) 20(10), 431-4

"Adapter proteins in lymphocyte antigen-receptor signaling"
PS Myung, NJ Boerthe and GA Koretzky
Curr Opin Immunol (2000) 12(3), 256-66

"Adaptors and molecular scaffolds in immune cell signaling"
CE Rudd
Cell (1999) 96(1), 5-8

"Lymphocyte signaling: adapting new adaptors"
CE Rudd
Curr Biol (1998) 8(22), 805-8

"The real LAT steps forward"
D Cantrell
Trends Cell Biol (1998) 8, 180-2

"The role of CD45 and CD45-associated molecules in T cell activation"
JG Altin and EK Sloan
Immunol Cell Biol (1997) 75(5), 430-45

"The role of membrane-associated adaptors in T cell receptor signalling"
W Zhang and LE Samelson
Semin Immunol (2000) 12(1), 35-41

"Intracellular adapter molecules"
LA Norian and GA Koretzky
Semin Immunol (2000) 12(1), 43-54

"Coupling the TCR to downstream signalling pathways: the role of cytoplasmic and transmembrane adaptor proteins"
A Marie-Cardine and B Schraven
Cell Signal (1999) 11(10), 705-12

"The role of SLP-76 and LAT in lymphocyte development"
VI Pivniouk and RS Geha
Curr Opin Immunol (2000) 12(2), 173-8

Apoptosis
"Apoptosis signaling in lymphocytes"
C Scaffidi, S Kirchhoff, PH Krammer and ME Peter
Curr Opin Immunol (1999) 11(3), 277-85

"Thymocyte apoptosis"
Y Yang and JD Ashwell
J Clin Immunol (1999) 19(6), 337-49

"Positive and negative thymocyte selection"
T Saito and N Watanabe
Crit Rev Immunol (1998) 18(4), 359-70