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A Site for CD4 Binding in the ß₁ Domain of the MHC Class II Protein HLA-DR1¹

Jennifer Brogdon^2,*, David D. Eckels, Christopher Davies, Stephen White and Carolyn Doyle^3,*

^* Department of Immunology, Duke University Medical Center, Durham, NC 27710; Blood Research Institute, The Blood Center, Milwaukee, WI; and Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN

Using a lymphocyte binding assay, we have previously demonstrated that the CD4 protein can mediate cell adhesion by direct interaction with MHC class II molecules. In this report, we have used this assay to test whether synthetic peptides, corresponding to DRß sequences, could inhibit CD4-class II adhesion. A peptide derived from sequences within the ß₁ domain (DRß41–55), as well as two peptides derived from sequences within the ß₂ domain (DRß121–135 and DRß141–155), were shown to inhibit CD4-class II adhesion. Inasmuch as a site for CD4 binding in the ß₂ domain had been previously documented, these studies were designed to investigate the role of the ß₁ domain as an additional site of interaction with CD4. Sixteen site-specific mutations were engineered within the ß₁ domain of DRß1*0101. Several mutations were shown to disrupt CD4-dependent T cell activation. Based on these results, we propose a model for the molecular interaction of CD4 with MHC class II proteins in which both the ß₁ and ß₂ domains of class II interact with the two amino-terminal Ig-like domains of CD4.

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