HLA-DR POLYMORPHISM AFFECTS THE INTERACTION WITH CD4

Major histocompatibility complex (MHC) class II molecules are highly p olymorphic and bind peptides for presentation to CD4(+) T cells. Funct ional and adhesion assays have shown that CD4 interacts with MHC class II molecules, leading to enhanced responses of CD4(+) T cells after t he activation of the CD4-associated tyrosine kinase p56(lck). We have addressed the possible contribution of allelic polymorphism in the int eraction between CD4 and MHC class II molecules. Using mouse DAP-3-tra nsfected cells expressing different isotypes and allelic forms of the HLA-DR molecule, we have shown in a functional assay that a hierarchy exists in the ability of class II molecules to interact with CD4. Also , the study of DR4 subtypes minimized the potential contribution of po lymorphic residues of the peptide-binding groove in the interaction wi th CD4. Chimeras between the DR4 or DR1 molecules, which interact effi ciently with CD4, and DRw53, which interacts poorly, allowed the mappi ng of polymorphic residues between positions beta 180 and 189 that can exert a dramatic influence on the interaction with CD4.