Definition of the alpha 2 region of HLA-DR molecules involved in CD4 binding

HLA class II molecules present antigenic peptides to the T cell receptor of CD4+ T lymphocytes and interact with CD4 during the antigen recognition pr ocess. A major CD4 binding site encompassing amino acids (aa) 134-148 in th e beta 2 domain of HLA-DR has been previously identified and residues locat ed within the alpha 2 subunit of murine MHC class II I-A(d) molecules have been shown to contribute to CD4-class II interaction. To characterize the a lpha 2 region of HLA-DR molecules involved in the binding of CD4, we have s ynthesized overlapping linear and cyclic peptides derived from a region enc ompassing aa 121-143. We demonstrate that two linear peptides (aa 124-138 a nd 130-143) and a cyclic one (aa 121-138) specifically bind to CD4-sepharos e affinity columns. Although cyclic analogues exhibit more ordered populati ons as detected by circular dichroism measurements, cyclization did not imp rove the activity of some peptides. Peptide sequence positioning in HLA-DR1 dimer model indicates that alpha 2 residues 124 to 136 form a solvent-expo sed loop which faces the beta 2 loop delimited by residues 134-148. These d ata suggest that one CD4 molecule contacts both alpha 2 and beta 2 loops of the HLA-DR homodimer. Human Immunology 60, 273-281 (1999). (C) American So ciety for Histocompatibility and Immunogenetics, 1999 Published by Elsevier Science Inc.