PIG MHC MEDIATES POSITIVE SELECTION OF MOUSE CD4(-CELLS WITH A MOUSE MHC-RESTRICTED TCR IN PIG THYMUS GRAFTS() T)

Remarkably normal immune function and specific T cell tolerance to dis cordant xenogeneic donors can be achieved by grafting fetal pig thymus and liver (FP THY/LIV) tissue to T cell and NK cell-depleted, thymect omized (ATX) mice. To determine whether or not host class II MHC molec ules participate in the positive selection of mouse CD4(+) T cells in FP THY/LIV grafts, ne compared their development in ATX, ''AND'' TCR-t ransgenic mice with positive selecting or nonselecting host MHC genoty pes, Mouse TCR-transgenic CD4 single positive T cells repopulated the periphery significantly and to a similar extent in both T/NK cell-depl eted, ATX AND mice with positive-selecting or nonselecting MHC backgro unds after grafting with FP THY/LIV. Therefore, MHC molecules from a w idely disparate xenogeneic species can positively select T cells beari ng a host class II MHC-restricted TCR without a contribution from the host MHC. These results, in combination with previous studies performe d in this model, suggest that the T cell repertoire that is generated by the combination of positive selection on xenogeneic MHC and negativ e selection on both recipient and xenogeneic porcine MHC is tolerant o f both donor and recipient and has sufficient cross-reactivity with ho st MHC/foreign peptide complexes to confer a high level of immunocompe tence. The results hale implications for the potential clinical applic ability of xenogeneic thymic transplantation and also suggest a predom inant role for the TCR recognition of species-conserved MHC residues i n positive selection.