Proline Residues in Cd28 and the Src Homology (Sh)3 Domain of Lck Are Required for T Cell Costimulation

doi:10.1084/jem.190.3.375

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© The Rockefeller University Press, 0022-1007/1999/8/375/ $5.00
The Journal of Experimental Medicine, Volume 190, Number 3, August 2, 1999 375-384

Original Article

Proline Residues in Cd28 and the Src Homology (Sh)3 Domain of Lck Are Required for T Cell Costimulation

Amy D. Holdorf^a, Jonathan M. Green^b, Steven D. Levin^c, Michael F. Denny^d, David B. Straus^d, Vinzenz Link^b, Paul S. Changelian^e, Paul M. Allen^a, and Andrey S. Shaw^a

^a From the Department of Pathology and Center for Immunology, Pulmonary Division, Washington University School of Medicine, St. Louis, Missouri 63110
^b From the Department of Medicine, Pulmonary Division, Washington University School of Medicine, St. Louis, Missouri 63110
^c Department of Immunology, University of Washington, Seattle, Washington 98195
^d Department of Medicine, University of Chicago, Chicago, Illinois 60637
^e Pfizer Central Research, Groton, Connecticut 06335
Dept. of Pathology, Box 8118, Washington University, 660 S. Euclid Ave., St. Louis, MO 63110.314-362-8888314-362-4614

shaw{at}immunology.wustl.edu

The Src family tyrosine kinases Lck and Fyn are critical forsignaling via the T cell receptor. However, the exact mechanismof their activation is unknown. Recent crystal structures ofSrc kinases suggest that an important mechanism of kinase activationis via engagement of the Src homology (SH)3 domain by proline-containingsequences. To test this hypothesis, we identified several Tcell membrane proteins that contain potential SH3 ligands. Herewe demonstrate that Lck and Fyn can be activated by prolinemotifs in the CD28 and CD2 proteins, respectively. Supportinga role for Lck in CD28 signaling, we demonstrate that CD28 signalingin both transformed and primary T cells requires Lck as wellas proline residues in CD28. These data suggest that Lck playsan essential role in CD28 costimulation.

Key Words: Lck • CD28 • costimulation • tyrosine kinase • SH3 domain

1used in this paper: GST, glutathione S transferase; ITAM, immunoreceptortyrosine-based activation motif; MAP, mitogen-activated protein;SH, Src homology

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