Phosphorylation of a tyrosine residue on Zap70 by Lck and its subsequent binding via an SH2 domain may be a key gatekeeper of T cell receptor signaling in vivo

Peter A. Thill, Arthur Weiss, Arup K. Chakraborty

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

The initiation of signaling in T lymphocytes in response to the binding of the T cell receptor (TCR) to cognate ligands is a key step in the emergence of adaptive immune responses. Conventional models posit that TCR signaling is initiated by the phosphorylation of receptor-associated immune receptor activation motifs (ITAMs). The cytoplasmic tyrosine kinase Zap70 binds to phosphorylated ITAMs, is subsequently activated, and then propagates downstream signaling. While evidence for such models is provided by experiments with cell lines, in vivo, Zap70 is bound to phosphorylated ITAMs in resting T cells. However, Zap70 is activated only upon TCR binding to cognate ligand. We report the results of computational studies of a new model for the initiation of TCR signaling that incorporates these in vivo observations. Importantly, the new model is shown to allow better and faster TCR discrimination between self-ligands and foreign ligands. The new model is consistent with many past experimental observations, and experiments that could further test the model are proposed.

Original languageEnglish
Pages (from-to)2396-2402
Number of pages7
JournalMolecular and Cellular Biology
Volume36
Issue number18
DOIs
StatePublished - 15 Sep 2016
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2016, American Society for Microbiology.

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