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Structural Relatedness of Distinct Determinants Recognized by Monoclonal Antibody TP25.99 on ß₂-Microglobulin-Associated and ß₂-Microglobulin-Free HLA Class I Heavy Chains¹

Smruti A. Desai^*, Xinhui Wang^*, Elvyra J. Noronha^*, Qinwei Zhou^*, Vera Rebmann, Hans Grosse-Wilde, Franklin J. Moy, Robert Powers and Soldano Ferrone^2,*

^* Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263; Institute for Immunology, University Hospital of Essen, Essen, Germany; and Department of Biological Chemistry, Wyeth-Ayerst Research, Cambridge, MA 02140

The association of HLA class I heavy chains with ß₂-microglobulin (ß₂m) changes their antigenic profile. As a result, Abs react with either ß₂m-free or ß₂m-associated HLA class I heavy chains. An exception to this rule is the mAb TP25.99, which reacts with both ß₂m-associated and ß₂m-free HLA class I heavy chains. The reactivity with ß₂m-associated HLA class I heavy chains is mediated by a conformational determinant expressed on all HLA-A, -B, and -C Ags. This determinant has been mapped to amino acid residues 194–198 in the 3 domain. The reactivity with ß₂m-free HLA class I heavy chains is mediated by a linear determinant expressed on all HLA-B Ags except the HLA-B73 allospecificity and on <50% of HLA-A allospecificities. The latter determinant has been mapped to amino acid residues 239–242, 245, and 246 in the 3 domain. The conformational and the linear determinants share several structural features, but have no homology in their amino acid sequence. mAb TP25.99 represents the first example of a mAb recognizing two distinct and spatially distant determinants on a protein. The structural homology of a linear and a conformational determinant on an antigenic entity provides a molecular mechanism for the sharing of specificity by B and TCRs.

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