THYMIC REPERTOIRE SELECTION BY SUPERANTIGENS - PRESENTATION BY HUMAN AND MOUSE MHC MOLECULES

The initial report of T cell receptor (TCR) V beta-specific thymic sel ection in mice showed association with expression of H-2E molecules an d affected V beta 17(a) T cells which were present in CD4(+)8(+) doubl e positive thymocytes but deleted from the CD4(+) and CD8(+) single po sitive populations. Similar deletions were subsequently reported for V beta 8.1(+) and V beta 6(+) T cells in Mls-l(a) mouse strains and for V beta 3(+) T cells in Mls-2(a)/3(a) strains. The 'Mls antigens' are most effectively presented by H-2E molecules but certain alleles of H- 2A molecules can also present these endogenous superantigens. Expressi on of Mls antigens can cause both V beta-specific thymic deletion and stimulation of peripheral T cells from Mls-negative strains. Another c ategory of 'Mls-like' antigens cause only V beta-specific thymic delet ion in H-2E(+) strains, affecting V beta 5(+) and V beta 11(+) T cells . The non-MHC ligands responsible for each of these effects are supera ntigens analogous to the exogenous bacterial superantigens, which also show TCR V beta-specific stimulatory effects when presented by MHC cl ass II positive antigen-presenting cells. The genes encoding endogenou s superantigens in mice were shown to co-segregate with mouse mammary tumour virus integrations (Mtv) and to be the Mtv-LTR orf genes. In vi tro translation of Mtv-LTR orf genes identified their products as type II integral membrane glycoproteins with the polymorphic C terminus ou tside the cell. These polymorphisms correlate with specificity for the different TCR V beta chains. Virtually all TCR V beta-specific negati ve selection in the mouse thymus can be accounted for by the expressio n of Mtv or MMTV (the infectious counterparts of Mtv proviral integran ts) LTR-orf proteins, presented with H-2E or certain H-2A alleles. It is unlikely that TCR V beta-specific positive selection is due to endo genous superantigens since it does not segegrate with Mtv genomes. In humans, HLA-DR molecules appear to be homologous with H-2E in mice whe reas HLA-DQ are the homologues of H-2A. H-2E negative mice transgenic for HLA-DR alpha chain express a mouse/human heterodimeric molecule wh ich presents Mtv superantigens causing TCR VP-specific deletion. Such trans-species class II molecules are also effective in TCR V beta-spec ific positive selection of V beta 2(+), V beta 6(+) and V beta 10(+) T cells. Taken together, these results show that human MHC class II mol ecules can interact with the murine T cell repertoire. In vivo effects of the expression of endogenous superantigens with DR alpha transgene s can differ from those with mouse H-2E alpha transgenes. A particular ly interesting example is the effect on susceptibility to the induced autoimmune disease experimental allergic encephalomyelitis.