Purified hematopoietic stem cell grafts induce tolerance to alloantigens and can mediate positive and negative T cell selection

Engraftment of allogeneic bone marrow (BM) has been shown to induce toleran ce to organs genotypically matched with the PM donor. Immune reconstitution after BM transplantation therefore involves re-establishment of a T cell p ool tolerant to antigens present on both donor and host tissues. However, h ow hematopoietic grafts exert their influence over the regenerating immune system is not completely understood. Prior studies suggest that education o f the newly arising T cell pool involves distinct contributions from donor and host stromal elements. Specifically, negative selection is thought to b e mediated primarily by donor PM-derived antigen-presenting cells, whereas positive selection is dictated by radio-resistant host-derived thymic strom al cells. In this report we studied the effect of highly purified allogenei c hematopoietic stem cells (HSCs) on organ transplantation tolerance induct ion and immune reconstitution. In contrast to engraftment of BM that result s in near-complete donor T cell chimerism, HSC engraftment results in mixed T cell chimerism. Nonetheless we observed that HSC grafts induce tolerance to donor-matched neonatal heart grafts, and one way the HSC grafts alter h ost immune responses is via deletion of newly arising donor as well as radi ation-resistant host T cells. Furthermore, using an in vivo assay of graft: rejection to study positive selection we made the unexpected observation t hat T cells in chimeric mice rejected grafts only in the context of the don or MHC type. These latter findings conflict with the conventionally held vi ew that radio-resistant host elements primarily dictate positive selection.