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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 186-194 |
| Number of pages | 9 |
| Journal | Nature immunology |
| Volume | 15 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 2014 |
Bibliographical note
Funding Information:We thank J.A. Bluestone (University of California, San Francisco) for CD80-CD86–deficient mice; J.B. Bolen (Moderna Therapeutics) for the anti-Lck hybridoma; H. Wang (University of California, San Francisco) for anti-ζ; A. Roque and Z. Wang for assisting with animal husbandry and cell sorting, respectively; N. Killeen and Z. Yang for technical assistance with BAC transgenesis; J.S. Shin for technical assistance with isolation of thymic DCs; H. Liu and the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center Mass Spectrometry Core Facility for technical and analytical expertise; and A. DeFranco, C. Lowell and H. Wang for critical reading of the manuscript and discussions. Supported by the Agency for Science, Technology and Research in Singapore (Y.X.T.), the Cancer Research Institute (B.N.M.) and the US National Institutes of Health (PO1 AI091580 to A.W. and 5R01EB001987 to K.M.S.).
