Alloreactive T-cell clones identify multiple HLA-DQw3 variants

Abstract

HLA-DQw3 is a broadly defined alloantigen that has been subdivided by serological, biochemical, and molecular methods into three distinct specificities: DQw7, DQw8, and DQw9. In order to characterize functionally relevant structural polymorphisms within this family of alloantigens, we generated a series of DQw3-reactive T-cell clones that together recognize six different variants of DQw3. T-cell clones IG11 and IG9 were found to recognize three distinct functional variants associated with a majority of DQw3+ cells, while clones 21J, IE6, 64B, and IC3 recognized four more narrowly distributed functional variants associated with unique DQw7, DQw8, and DQw9 subsets. Comparison of known DQB gene sequences suggested candidate recognition sites for clones IG11 and 64B in the region of amino acid residues 66 to 71 and residue 57 of the DQ beta chain. In contrast, no unique DQB or DQA sequences were found that individually corresponded to the reactivity patterns of clones 21J, IE6, IG9, or IC3, suggesting that an interaction between DQ alpha and DQ beta chains determines allo-recognition. These data are consistent with the hypothesis that T cells recognize specific alloepitopes on HLA class II molecules, either as distinct structural elements that trigger an alloresponse or, more indirectly, as contact elements that influence alloreactivity by governing the binding of foreign peptide. The results illustrate the diversity of possible T cell responses directed toward HLA-DQ molecules and suggest that T cell recognition of the DQ heterodimer alone, or a peptide antigen bound to the DQ heterodimer, can be affected either by the individual DQ alpha and beta chains, or by a more complex interaction between the two.