POSITIVE AND NEGATIVE SELECTION OF FUNCTIONAL-MOUSE CD4 CELLS BY PORCINE MHC IN PIG THYMUS GRAFTS

Specific tolerance to discordant xenogeneic donors can be achieved by grafting of fetal pig thymic and liver tissue (FP THY/LIV) to T cell a nd NK cell-depleted, thymectomized (ATX) mice, Mouse CD4(+) T cells de velop in FP THY/LIV grafts, and demonstrate remarkably normal immune f unction, including host-restricted responses to keyhole limpet hemocya nin, We have therefore studied the role of host MHC class II in the de velopment of mouse T cells in FP THY/LIV grafts by comparing their dev elopment in ATX MHC class Il-deficient (IIKO) and wild-type (H-2(b)) m ice, Mouse CD4(+) T cells repopulated T/NK cell-depleted, ATX IIKO mic e after grafting with FP THY/LIV, indicating that pig MHC can positive ly select mouse CD4 cells, Expression of TCR, MHC class I, Qa-2, heat- stable Ag, and CD45RB among double-positive and CD4 single-positive (S P) graft thymocytes in wild-type recipients was similar to that in nor mal mouse thymi, whereas CD4 SP thymocytes in grafts of IIKO mice show ed increased Qa-2 and decreased heat-stable Ag expression, suggesting an increased level of maturity, Double-positive cells in grafts of IIK O mice also expressed higher than normal levels of Qa-2. Deletion with in the grafts of V beta 3(+), V beta 5.1/5.2(+), and V beta 11(+) but not V beta 6(+), V beta 7(+), or V beta 8.1/8.2(+) mouse CD4 SP thymoc ytes in ATX IIKO mice demonstrated that swine leukocyte Bg participate s in negative selection of the T cell repertoire, Therefore, porcine M HC mediates positive and negative selection of mouse thymocytes, but h ost class II MHC molecules also regulate thymocyte maturation in xenog eneic thymic grafts.