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Nat Immunol. 2014 Feb;15(2):186-94. doi: 10.1038/ni.2772. Epub 2013 Dec 8.

Inhibition of the kinase Csk in thymocytes reveals a requirement for actin remodeling in the initiation of full TCR signaling.

Author information

1
Rosalind Russell-Ephraim P. Engleman Medical Research Center for Arthritis, Division of Rheumatology, Department of Medicine, University of California, San Francisco, California, USA.
2
Department of Chemistry, University of Southern California, California, USA.
3
1] Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
4
1] Rosalind Russell-Ephraim P. Engleman Medical Research Center for Arthritis, Division of Rheumatology, Department of Medicine, University of California, San Francisco, California, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA. [3] Department of Microbiology and Immunology, University of California, San Francisco, California, USA.

Abstract

Signaling via the T cell antigen receptor (TCR) is initiated by Src-family kinases (SFKs). To understand how the kinase Csk, a negative regulator of SFKs, controls the basal state and the initiation of TCR signaling, we generated mice that express a Csk variant sensitive to an analog of the common kinase inhibitor PP1 (Csk(AS)). Inhibition of Csk(AS) in thymocytes, without engagement of the TCR, induced potent activation of SFKs and proximal TCR signaling up to phospholipase C-γ1 (PLC-γ1). Unexpectedly, increases in inositol phosphates, intracellular calcium and phosphorylation of the kinase Erk were impaired. Altering the actin cytoskeleton pharmacologically or providing costimulation via CD28 'rescued' those defects. Thus, Csk has a critical role in preventing TCR signaling. However, our studies also revealed a requirement for actin remodeling, initiated by costimulation, for full TCR signaling.

Comment in

PMID:
24317039
PMCID:
PMC3946925
DOI:
10.1038/ni.2772
[Indexed for MEDLINE]
Free PMC Article

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