title: Minor histocompatibility antigens HA-1-, -2-, and -4-, and HY-specific cytotoxic T-cell clones inhibit human hematopoietic progenitor cell growth by a mechanism that is dependent on direct cell-cell contact.
abstract: HLA-identical bone marrow transplantation (BMT) may be complicated by graft-versus-host disease or graft rejection. Both complications are thought to be initiated by recognition of minor histocompatibility (mH) antigens by HLA-restricted mH-antigen-specific T lymphocytes. Using HLA-A2-restricted mH antigens HA-1-, -2-, and -4-, and HY-specific cytotoxic T lymphocyte (CTL) clones, we studied the recognition by these CTL clones of interleukin-2 (IL-2)-stimulated T cells (IL-2 blasts), BM mononuclear cells (BMMNCs), and hematopoietic progenitor cells (HPCs). We showed that, when IL-2 blasts from the BM donors who were investigated were recognized by the HA-1-, -2-, and -4-, and HY-specific CTL clones, their BMMNCs and HPCs were recognized as well by these CTL clones, resulting in antigen-specific growth inhibition of erythrocyte burst-forming units (BFU-E), colony-forming units-granulocyte (CFU-G), and CFU-macrophage (CFU-M). the HA-2-specific CTL clone, however, inhibited BFU-E and CFU-G growth from four donors to a lesser extent than from two other donors. We further investigated whether inhibitory cytokines released into the culture medium by the antigen-specific stimulated CTLs or by stimulated BMMNCs were responsible for suppression of HPC growth or whether this effect was caused by direct cell-cell contact between CTLs and HPCs. HPC growth inhibition was only observed after preincubation of BMMNCs and CTLs together for 4 hours before plating the cells in semisolid HPC culture medium. When no cell-cell contact was permitted before plating, neither antigen-stimulated CTL nor antigen-nonstimulated CTLs provoked HPC growth inhibition. Culturing BMMNCs in the presence of supernatants harvested after incubation of BMMNCs and CTL clones together for 4 or 72 hours did also not result in HPC growth inhibition. Both suppression of HPC growth and lysis of IL-2 blasts and BMMNCs in the 51Cr-release assay appeared to be dependent on direct cell-cell contact between target cells and CTLs and were not caused by the release of inhibitory cytokines into the culture medium by antigen-specific stimulated CTLs or by stimulated BMMNCs. Our results show that mH-antigen-specific CTLs can inhibit HPC growth by a direct cytolytic effect and may therefore be responsible for BM graft rejection after HLA-identical BMT.
authors.affiliation: Department of Hematology, University Medical Center, Leiden, The Netherlands.
authors.forename: W A
authors.initials: WA
authors.lastname: Marijt
authors.forename: W F
authors.initials: WF
authors.lastname: Veenhof
authors.forename: E
authors.initials: E
authors.lastname: Goulmy
authors.forename: R
authors.initials: R
authors.lastname: Willemze
authors.forename: J J
authors.initials: JJ
authors.lastname: van Rood
authors.forename: J H
authors.initials: JH
authors.lastname: Falkenburg
mesh_terms: D001854:Bone Marrow Cells; D016026:Bone Marrow Transplantation / Q000276:immunology; D002455:Cell Division; D006084:Graft Rejection / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology; D006182:H-Y Antigen / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000276:immunology; D006650:Histocompatibility Testing; D006801:Humans; D015778:Minor Histocompatibility Antigens / Q000502:physiology*; D009363:Neoplasm Proteins / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000502:physiology*
chemical_list: D006182:H-Y Antigen; C080145:HA-2 antigen; D015778:Minor Histocompatibility Antigens; D009363:Neoplasm Proteins