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Review
. 2018 Jan;153(1):42-50.
doi: 10.1111/imm.12809. Epub 2017 Sep 5.

Selected signalling proteins recruited to the T-cell receptor-CD3 complex

Jatuporn Ngoenkam  1 , Wolfgang W Schamel  2   3   4 , Sutatip Pongcharoen  5   6   7
Affiliations
Review

Selected signalling proteins recruited to the T-cell receptor-CD3 complex

Jatuporn Ngoenkam et al. Immunology. 2018 Jan.

Abstract

The T-cell receptor (TCR)-CD3 complex, expressed on T cells, determines the outcome of a T-cell response. It consists of the TCR-αβ heterodimer and the non-covalently associated signalling dimers of CD3εγ, CD3εδ and CD3ζζ. TCR-αβ binds specifically to a cognate peptide antigen bound to an MHC molecule, whereas the CD3 subunits transmit the signal into the cytosol to activate signalling events. Recruitment of proteins to specialized localizations is one mechanism to regulate activation and termination of signalling. In the last 25 years a large number of signalling molecules recruited to the TCR-CD3 complex upon antigen binding to TCR-αβ have been described. Here, we review knowledge about five of those interaction partners: Lck, ZAP-70, Nck, WASP and Numb. Some of these proteins have been targeted in the development of immunomodulatory drugs aiming to treat patients with autoimmune diseases and organ transplants.

Keywords: T-cell activation; T-cell receptor-CD3 complex; protein-protein interaction; signal transduction.

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Figures

Figure 1
Figure 1
Modular composition of proteins associated with the T‐cell receptor (TCR) –CD3 complex. (a) Lck consists of an Src homology 4 (SH4) domain, a unique domain, an SH3 and SH2 domain, the catalytic domain and a C‐terminal region. The serine (S) and tyrosines (Y) depicted can be phosphorylated upon TCR–CD3 ligation. (b) ZAP‐70 contains an N‐terminal SH2 domain, an interdomain A (IA), a C‐terminal SH2 domain, an interdomain B (IB) and the kinase domain. The tyrosine residues indicated can be phosphorylated upon TCR–CD3 triggering. (c) The Nck family has two members, Nck1 and Nck2, both being composed of three SH3 domains and a C‐terminal SH2 domain. (d) WASP consists of a WH1 (WASP homology 1) and basic domain, followed by a GTPase‐binding domain (GBD), a proline‐rich sequence (PRS) and verprolin homology domain–cofilin homology domain‐acidic region domains (VCA). (e) Numb contains a phospho‐tyrosine binding (PTB) domain, two PRSs and DPF (Asp‐Pro‐Phe) and NPF (Asn‐Pro‐Phe) tri‐peptide motifs at the C‐terminus.
Figure 2
Figure 2
Selected signalling proteins at TCR–CD3 complex. TCR–CD3 ligation induces a conformational change of CD3ε, leading to the exposure of its proline‐rich sequence (PRS). Nck is then recruited to the PRS within the cytoplasmic tail of the CD3ε. Subsequently, Lck is associated with Nck upon TCR activation. Hence, Nck recruitment to TCR may also bring Lck to TCR–CD3 complex to mediate phosphorylation of the ITAM motif. In addition, Lck can directly interact with phospho‐ITAM. When the second tyrosine of the CD3ε ITAM is phosphorylated, Nck can bind with CD3ε using its SH3.1 and SH2 domains in a co‐operative manner. In proximity to the TCR–CD3 complex, Lck phosphorylates tyrosines in each ITAM of the CD3 chains. ZAP‐70 is then recruited to bind to the phospho‐ITAMs, where ZAP‐70 itself is phosphorylated by Lck. WASP can be associated with Nck upon TCR activation to regulate actin polymerization. Numb can be associated with the CD3ε to regulate in TCR degradation leading to a decrease in TCR signalling.
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