T cell receptor signalling networks: branched, diversified and bounded

Abstract

Engagement of antigen-specific T cell receptors (TCRs) is a prerequisite for T cell activation. Acquisition of appropriate effector T cell function requires the participation of multiple signals from the T cell microenvironment. Trying to understand how these signals integrate to achieve specific functional outcomes while maintaining tolerance to self is a major challenge in lymphocyte biology. Several recent publications have provided important insights into how dysregulation of T cell signalling and the development of autoreactivity can result if the branching and integration of signalling pathways are perturbed. We discuss how these findings highlight the importance of spatial segregation of individual signalling components as a way of regulating T cell responsiveness and immune tolerance.

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose

“…It is also appreciated that the pMHC dose determines, for example, the peripheral induction of regulatory T cells (4,5). Although the proteins that form the TCRregulated signaling network have been identified (6,7), it remains unclear how the architecture they form integrates the pMHC affinity and dose into T-cell activation (8,9).…”

USP8 – Another DUB in the T cell club

“…4 Our studies did not reveal a defect in TCR-induced canonical signaling cascades. However, whether USP8 is involved in the discrimination of low-and high-affinity signals in specific thymocyte populations remains to be tested.…”

“…3 Gads is highly abundant in T cells and modulates signal diversification. 4 As typical for 14-3-3 proteins, the interaction with 14-3-3b was dependent on a serine phosphorylation motif within the 14-3-3 binding motif (14-3-3BM) of USP8 (Fig. 1).…”

Molecular characterization and expression of ZAP-70 in Nile tilapia (Oreochromis niloticus) in response to Streptococcus agalactiae stimulus

“…The TCRs has no intrinsic enzymatic activity and instead depends on the kinase activity of a series of protein tyrosine kinases, to initiate signaling (Davis et al 2003;Smith-Garvin et al 2009). Among these kinases, the 70 kDa zeta-chain associated protein kinase (ZAP-70), one of members of the Syk kinase family, plays a critical role in effective signal transduction from TCRs (Brownlie and Zamoyska 2013;Wang et al 2010). Upon T-cell activation, lymphocyte-specific protein tyrosine kinase (Lck) phosphorylates immunoreceptor tyrosinebased activation motifs (ITAMs) of the CD3 and TCR-f chain, and these phosphorylated ITAMs become high affinity docking sites for ZAP-70, which is also phosphorylated and activated by Lck (van Oers et al 1996).…”