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 Previous Article

Molecular and Cellular Biology, September 2006, p. 6727-6738, Vol. 26, No. 17
0270-7306/06/$08.00+0     doi:10.1128/MCB.00688-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

CD6 Regulates T-Cell Responses through Activation-Dependent Recruitment of the Positive Regulator SLP-76

Namir J. Hassan,1,{dagger} Stephen J. Simmonds,1 Nicholas G. Clarkson,1 Sarah Hanrahan,2 Michael J. Puklavec,1 Martine Bomb,1 A. Neil Barclay,1 and Marion H. Brown1*

Sir William Dunn School of Pathology, South Parks Rd., Oxford, United Kingdom,1 Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, London, United Kingdom2

Received 21 April 2006/ Accepted 6 June 2006

Deciphering the role of lymphocyte membrane proteins depends on dissecting the role of a protein in the steady state and on engagement with its ligand. We show that expression of CD6 in T cells limits their responsiveness but that engagement by the physiological ligand CD166 gives costimulation. This costimulatory effect of CD6 is mediated through phosphorylation-dependent binding of a specific tyrosine residue, 662Y, in its cytoplasmic region to the adaptor SLP-76. A direct interaction between SLP-76 and CD6 was shown by binding both to a phosphorylated peptide (equilibrium dissociation constant [KD] = 0.5 µM at 37°C) and, using a novel approach, to native phosphorylated CD6. Evidence that CD6 and SLP-76 interact in cells was obtained in coprecipitation experiments with normal human T cells. Analysis of human CD6 mutants in a murine T-cell hybridoma model showed that both costimulation by CD6 and the interaction between CD6 and SLP-76 were dependent on 662Y. The results have implications for regulation by CD6 and the related T-cell surface protein, CD5.

* Corresponding author. Mailing address: Sir William Dunn School of Pathology, South Parks Rd., Oxford, OX1 3RE, United Kingdom. Phone: 01865 275595. Fax: 01865 275591. E-mail: Marion.Brown{at}path.ox.ac.uk.

{dagger} Present address: GlaxoSmithKline, Harlow, United Kingdom.

Molecular and Cellular Biology, September 2006, p. 6727-6738, Vol. 26, No. 17
0270-7306/06/$08.00+0     doi:10.1128/MCB.00688-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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