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T hough the first association between HLA and disease was established with an HLA class I molecule (1), the majority of HLA-disease associations have been with HLA dass II molecules (2). Despite the awareness of such associations for nearly two decades, the pathophysiological role of HLA class II molecules in conferring susceptibility to the associated diseases remains poorly understood. One impediment to enhancing our understanding has been the inability to study the function of human class II molecules in animal models where experimental manipulations can be readily accomplished. Two papers in this issue of The Journal of Experimental Medicine, by Woods et al. (3) and Yamamoto et al. (4), now document the successful construction of transgenic mice bearing chimeric or whole human DR and DQ molecules, and further demonstrate that murine T cells are capable of recognizing antigenic peptides presented by human class II molecules. In addition, the results obtained by Yamamoto et al. (4) dispel the notion that murine CD4 on murine T cells cannot function as an adequate accessory molecule during peptide presentation by human class II molecules. This concept has undoubtedly slowed progress in this much needed area. T lymphocyte activation is initiated through recognition of a peptide-MHC molecule ligand residing on the antigenpresenting cell by the antigen-specific receptor residing on the T lymphocyte. However, optimization of the activation is achieved through a series of accessory and adhesion molecules, among which is the CD4 molecule (5). CD4 was initially identified on the surface of a subset of T lymphocytes by monoclonal antibodies, and its presence was used to study the functions of this subset. Antibodies against the 55kilodalton CD4 glycoprotein were demonstrated to block the majority of helper T cell functions, including mixed lymphocyte reactions and induction of helper activity (6-8). These observations suggested that CD4 was therefore a marker for the helper T cell population. However, several laboratories subsequently demonstrated that the subset of cytotoxic T cells that recognized class II molecules bore CD4 (9, 10) and that monoclonal antibodies to CD4 could block the function of any T cells specific for class II molecules (11). These findings led to the currently held concept that CD4 positive T cells possess receptors that recognize peptide in the context of class II molecules, irrespective of their functions. CD4 was demonstrated to interact with class II molecules both by functional studies and direct binding (12, 13). The

HLA class II transgenic mice: the chance to unravel the basis of HLA class II associations with disease.