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 Vβ5 and Vα2 determinants, while no differences in the abundance of of TcR Vβ6, Vβ8 and Vβ12 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.