We have constructed transgenic mice that express the human class II YHC molecule HLA-DRa on a genetic background in which the equivalent endogenous gene, H-2 IEa, is not expressed. In these mice, DRa complemented the E5 chain such that tissue-specific expression of an interspecies hybrid DRa-E5 heterodimer was obtained. Despite 25% amino acid differences between DRa and Ea, immune responsiveness to IE-controlled antigens, clonal deletion of IE-reactive T cells, and alloantigenicity were quantitatively and qualitatively indistinguishable in IE-positive mice and in mice that had integrated at least four copies of the transgene. These results demonstrate a remarkable degree of structural, regulatory, and functional conservation. They also suggest that tolerance induction involves only discrete portions of MHC molecules. introduction

Major histocompatibility complex (MHC) class II gene products are cell surface heterodimeric glycoproteins composed of 34 kd a and 29 kd 8 chains. These molecules play a crucial role in the immunological processes of selftolerance, MHC restriction, and antigen presentation (reviewed in Klein, 1986). Each of these processes involves the interaction of MHC molecules with antigen, T cell a-8 receptors (TCRs), and accessory molecules such as CD4. The relationship between these interactions and the biology of tolerance induction and MHC-restricted antigen presentation is, however, poorly understood. Both MHC and TCR gene products are characterized by extensive structural complexity (see Klein, 1986). An important functional consequence of this complexity is diversity in antigen recognition. In the evolution of independent mammalian species, MHC and TCR complexes have diverged significantly in gene structure, number, and regulation (Figure 1). These observations led us to explore the potential for in vivo interspecies interactions between human and murine MHC and TCR molecules. Certain strains of mice, denoted E”(Dembic et al., 1984), lack IE expression and IE-controlled immune functions because of mutations inactivating one or more of the IE genes (Mathis et al., 1983). Ea” mice express E9, but it is found only intracellularly (Murphy et al., 1980). Cell surface expression and immunological function can be re-