RESTRICTED EXPRESSION OF TRANSGENIC HLA-DRA GENE IN THYMIC EPITHELIAL-CELLS AND ITS ROLE IN ACQUISITION OF T-CELL TOLERANCE TO SELF-SUPERANTIGENS AND PROCESSED DR-ALPHA-DERIVED PEPTIDE

We have established a set of transgenic mouse lines in which the HLA-DRA gene was expressed in different cell types. In one line (DRalpha-24), DRalphaEbeta(b) molecules were expressed on thymic medullary and cortical epithelial cells and all lineages of bone marrow-derived antigen-presenting cells (APC) except for thymic macrophages. By contrast, expression of the molecules in another line (DRalpha-30) was found on thymic medullary and cortical epithelial cells but not on bone marrow-derived APC in the thymus and periphery. To evaluate the role of thymic epithelial cells in acquisition of T cell tolerance, comparative analysis of DRalpha-24 and DRalpha-30 was performed. In DRalpha-30, T cells expressing TcR Vbeta5 and Vbeta11 were eliminated to comparable levels to those in DRalpha-24, suggesting that expression of the DRalphaEbeta(b) molecules on thymic epithelial cells are sufficient for clonal deletion of the self-superantigen-reactive T cells. In addition, CD4+ T cells from DRalpha-30 as well as those from DRalpha-24 were tolerant to DRalpha-derived peptide/I-A(b) complex expressed on spleen cells from DRalpha-24 even in the presence of exogenous interleukin-2. These observations suggest that expression of the DRalpha chain in thymic epithelial cells could induce T cell tolerance directed toward naturally processed DRalpha-derived peptide bound to I-A(b) molecules, probably via clonal deletion of the self-reactive T cells.