CD6 regulates T-cell responses through activation-dependent recruitment of the positive regulator SLP-76

NJ Hassan, SJ Simmonds, NG Clarkson… - … and cellular biology, 2006 - Am Soc Microbiol
NJ Hassan, SJ Simmonds, NG Clarkson, S Hanrahan, MJ Puklavec, M Bomb, AN Barclay
Molecular and cellular biology, 2006Am Soc Microbiol
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 …
Abstract
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 [K D]= 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.
American Society for Microbiology