THE T-CELL RESPONSE OF HLA-DR TRANSGENIC MICE TO HUMAN MYELIN BASIC-PROTEIN AND OTHER ANTIGENS IN THE PRESENCE AND ABSENCE OF HUMAN CD4

Analysis of HLA class II transgenic mice has progressed in recent year s from analysis of single chain HLA class II transgenes with expressio n of mixed mouse/human heterodimers to double transgenic mice expressi ng normal human heterodimers. Previous studies have used either HLA tr ansgenic mice in which there is a species-matched interaction with CD4 or mice which lack this interaction. Since both systems are reported to generate HLA-restricted responses, the matter of the requirement fo r species-matched CD4 remains unclear. We have generated triple transg enic mice expressing three human transgenes, DRA, DRB, and CD4, and co mpared HLA-restricted responses to peptide between human-CD4(+) (Hu-CD 4(+)) and Hu-CD4(-) littermates. We saw no difference between Hu-CD4() and Hu-CD4(-) groups, supporting the notion that for some responses at least the requirement for species-matched CD4 may not be absolute. Evidence for positive selection of mouse T cell receptors in HLA-DR tr ansgenic mice came both from the acquisition of new, HLA-restricted re sponses to various peptides and from an increased frequency of T cells using the TCR V beta 4 gene segment. An important goal with respect t o the analysis of function in HLA transgenic mice is the clarification of mechanisms which underpin the recognition of self-antigens in huma n autoimmune disease. As a first step towards 'humanized' disease mode ls in HLA transgenic mice, we analyzed the responses of HLA-DR transge nic mice to the human MPB 139-154 peptide which has been implicated as an epitope recognized by T cells of multiple sclerosis patients. We o btained T cell responses to this epitope in transgenic mice but not in nontransgenic controls. This study suggests that HLA transgenic mice will be valuable in the analysis of HLA-restricted T cell epitopes imp licated in human disease and possibly in the design of new disease mod els.