The Journal of Experimental Medicine
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Published online 20 February 2001.
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© The Rockefeller University Press, 0022-1007/2001/2/497/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 4, February 19, 2001 497-508

Original Article

Activation of the COOH-terminal Src kinase (Csk) by cAMP-dependent Protein Kinase Inhibits Signaling through the T Cell Receptor

Torkel Vanga, Knut Martin Torgersena, Vibeke Sundvoldb, Manju Saxenac, Finn Olav Levya, Bjørn S. Skålhegga, Vidar Hanssona, Tomas Mustelinc,d, and Kjetil Taskéna
a Department of Medical Biochemistry, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway
b Institute of Immunology, University of Oslo, The National Hospital, N-0027 Oslo, Norway
c La Jolla Institute for Allergy and Immunology, San Diego, California 92121
d La Jolla Cancer Research Center, The Burnham Institute, La Jolla, California 92037

Correspondence to: Tomas Mustelin, La Jolla Cancer Center, The Burnham Institute, 70901 North Torrey Pines Rd., La Jolla, CA 92037. Tel:858-713-6270 Fax:858-713-6274 E-mail:tmustelin{at}burnham-inst.org.

In T cells, cAMP-dependent protein kinase (PKA) type I colocalizes with the T cell receptor–CD3 complex (TCR/CD3) and inhibits T cell function via a previously unknown proximal target. Here we examine the mechanism for this PKA-mediated immunomodulation. cAMP treatment of Jurkat and normal T cells reduces Lck-mediated tyrosine phosphorylation of the TCR/CD3 {zeta} chain after T cell activation, and decreases Lck activity. Phosphorylation of residue Y505 in Lck by COOH-terminal Src kinase (Csk), which negatively regulates Lck, is essential for the inhibitory effect of cAMP on {zeta} chain phosphorylation. PKA phosphorylates Csk at S364 in vitro and in vivo leading to a two- to fourfold increase in Csk activity that is necessary for cAMP-mediated inhibition of TCR-induced interleukin 2 secretion. Both PKA type I and Csk are targeted to lipid rafts where proximal T cell activation occurs, and phosphorylation of raft-associated Lck by Csk is increased in cells treated with forskolin. We propose a mechanism whereby PKA through activation of Csk intersects signaling by Src kinases and inhibits T cell activation.

Key Words: protein kinase A, Csk, T cell activation, tyrosine phosphorylation, immunomodulation


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