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

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.

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Second Correction for Hassan et al., “CD6 Regulates T-Cell Responses through Activation-Dependent Recruitment of the Positive Regulator SLP-76”

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

We thank Anton van der Merwe, Gary Brooke, and Nigel Killeen for helpful discussions. We are extremely grateful to Vaclav Horejsi for providing us with generous amounts of the high-affinity CD6 mAb, MEM-98 mAb.

The authors have no conflicting financial interests.

The work was supported by the Medical Research Council.