Scaffolding of Proximal TCR Signaling

The T-cell receptor is composed of a ligand-binding TCRaP heterodimer and signal-transducing dimers of CD3ey, CD3e§ and ZZ that upon interaction with its MHC-peptide ligand initiate an activation process that probably involves both receptor clustering and conformational change of the cytoplasmic part of the CD3 component (Call and Wucherpfennig 2005; Minguet et al. 2007). These signaling components contain ITAMs with the consensus sequence YxxL/I/V x(6-8) YxxL/I/V that are essential for TCR-mediated activation (Reth 1989). The tyrosine residues within this motif are phosphorylated by the protein tyrosine kinases Lck and Fyn and play a critical role in the recruitment of Src homology 2 (SH2) domain-containing proteins to the TCR (Chan and Shaw 1996; Kane et al. 2000). In this respect, the receptor itself acts as an adaptor where specific assembly of signaling components can be regulated. Phosphorylated ITAMs recruit the tandem SH2-containing tyrosine kinase Zap-70 that is further regulated by a complex interplay between the tyrosine kinases Lck and Abl (Chu et al. 1998; Zipfel et al. 2004). In addition to phosphorylation in the activation loop of the kinase, several regulatory events have been coupled to tyrosine phosphorylation sites in interdomain B of Zap-70, between the second SH2 domain and the kinase domain (Brdicka et al. 2005; Deindl et al. 2007; Di et al. 1999; Pelosi et al. 1999). This includes the recruitment of several adaptor proteins, such as c-Cbl, Vav and Crk, that can direct the activation process, suggesting that protein assembly at the level of Zap-70 is functionally important both in developing and mature cells. In support of this notion, Zap-70-deficient mice fail to develop mature T cells, and humans harboring mutations in the Zap-70 gene develop a severe form of immune deficiency due to the lack of circulating CD8+ cells and functional CD4+ cells (Negishi et al. 1995; Wiest et al. 1997). An interesting observation that further illustrates the importance of intact Zap-70 recruitment is seen in SKG mice that carry a single nucleotide substitution in the second SH2 domain of Zap-70 (W163C). These mice develop an autoimmune disease resembling human rheumatoid arthritis, probably due to a switch in the selection process that leads to survival of T cells with a high degree of self-reactivity (Sakaguchi et al. 2003, 2006b). Importantly, the disease does not manifest itself until T cells in the periphery are activated by pathogens, suggesting that only then is the higher self-reactivity able to overcome the reduced signaling ability. Hence, it seems that a partial defect in Zap-70 is enough to change the signaling threshold essential for correct thymic selection. This suggests that fine-tuning of signals is functionally very important in balancing immune regulation. Other immunoreceptors that utilize ITAM phosphorylation and recruitment of Syk family tyrosine kinases include the B-cell receptor (BCR), Fc receptors for IgG (FcyRIII and FceRI) and the collagen receptor on platelets, indicating that the ITAM-mediated recruitment of tandem SH2-containing kinases is a general paradigm for transmitting signals in response to immunoreceptor-ligand interaction (Underhill and Goodridge 2007). Following the recruitment and activation of Zap-70, the TCR represents an activated immune receptor that is ready to initiate downstream signals. The next step in immune cell signaling is to connect the activated receptor complex to relevant downstream pathways to elicit adequate immune responses. This involves the specific recruitment of different signaling components to the inner leaflet of the plasma membrane through a highly sophisticated network of protein interactions.

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