Self-nonself discrimination and repertoire selection of human T cells differentiated in an HLA-semiallogeneic environment following bone marrow transplantation for severe combined immunodeficiency.

We have analyzed allorecognition, HLA restriction and T cell receptor (TcR) diversity in an HLA-heterozygous (HLA-DRw6,7) severe combined immunodeficiency (SCID) patient whose T cell system had been repopulated by HLA-homozygous (HLA-DRw6) paternal T cells following T cell-depleted bone marrow transplantation (BMT). Donor origin of T cells and host origin of antigen-presenting cells (APC) in peripheral blood and BM is shown by HLA typing of separated cell populations and two-color immunofluorescence using an anti-HLA monoclonal antibody (mAb). Peripheral blood lymphocytes (PBL) from the chimeric patient proliferate normally against PHA, anti-TcR/CD3 mAb, pooled allogeneic PBL, and also against the recall antigen (Ag) tetanus toxoid and purified protein derivative of tuberculin (PPD) following immunization, suggesting recognition by donor (DRw6) T cells of Ag presented by host (DRw6,7) APC. PPD-specific cytotoxic T lymphocytes generated in vitro from patient PBL post-BMT display specific cytotoxicity against targets expressing DRw6 and DR7, but not against DR-mismatched targets, suggesting that HLA restriction of Ag recognition may occur through determinants expressed by the host and not by the donor. Donor T cells differentiated in the HLA-semiallogeneic host show specific proliferative and cytotoxic responses against HLA-mismatched stimulators, but not against stimulators taken from the host, expressing the host-specific HLA-haplotype, or expressing the host-specific HLA-DR7 antigens. Compared to T cells directly taken from the donor, differentiation of donor T cells in the host is associated with a significant decrease of T cells expressing TcR V beta 5 and V alpha 2 determinants, while no differences in the abundance of of TcR V beta 6, V beta 8 and V beta 12 subsets were noticed. We conclude that allorecognition, major histocompatibility complex (MHC) restriction and TcR diversity generation of human T cells can be modulated through differentiation in an MHC-different environment, as had been previously shown to be the case in murine model systems.