Abstract
Signaling through the T cell receptor (TCR) initiates adaptive immunity and its perturbation may results in autoimmunity. The plasma membrane scaffolding protein LAT acts as a central organizer of the TCR signaling machinery to activate many functional pathways. LAT-deficient mice develop an autoimmune syndrome but the mechanism of this pathology is unknown. In this work we have compared global dynamics of TCR signaling by MS-based quantitative phosphoproteomics in LAT-sufficient and LAT-defective Jurkat T cells. Surprisingly, we found that many TCR-induced phosphorylation events persist in the absence of LAT, despite ERK and PLCγ1 phosphorylation being repressed. Most importantly, the absence of LAT resulted in augmented and persistent tyrosine phosphorylation of CD3ζ and ZAP70. This indicates that LAT signaling hub is also implicated in negative feedback signals to modulate upstream phosphorylation events. Phosphorylation kinetics data resulting from this investigation is documented in a database (phosphoTCR) accessible online. The MS data have been deposited to the ProteomeXchange with identifier PXD000341.
Highlights
The T cell receptor (TCR) plays a central role in adoptive immunity through signaling processes that dictate T cell fate during development and upon exposure to antigen
Signals triggered by TCR ligation with peptide-MHC complex are translated into intracellular phosphorylation events by Src and Syk family protein tyrosine kinases (PTK) LCK and ZAP70, respectively
While LAT-signalosome triggers mostly forward positive signaling, it has been hypothesized that immune disorders could be unleashed by the removal of negative feedback mechanism in TCR signaling associated to LAT [5]
Summary
The T cell receptor (TCR) plays a central role in adoptive immunity through signaling processes that dictate T cell fate during development and upon exposure to antigen. Signals triggered by TCR ligation with peptide-MHC complex are translated into intracellular phosphorylation events by Src and Syk family protein tyrosine kinases (PTK) LCK and ZAP70, respectively. Tyrosine phosphorylation of LAT (The Linker for Activation of T cell) allows the recruitment of signaling protein complexes that activate all major signaling pathways, regulating T cell functions [1]. Point mutation of LAT at Y136, the PLCc-1 binding site, causes massive lymphoproliferation and autoimmunity in mice [3,4]. These same disorders are caused by conditional LAT-deletion or expression of LAT mutated at Y136 in peripheral T cells of mice. While LAT-signalosome triggers mostly forward positive signaling, it has been hypothesized that immune disorders could be unleashed by the removal of negative feedback mechanism in TCR signaling associated to LAT [5]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
