title: Antigen-primed CD8+ T cells can mediate resistance, preventing allogeneic marrow engraftment in the simultaneous absence of perforin-, CD95L-, TNFR1-, and TRAIL-dependent killing.
abstract: Engraftment failure following allogeneic bone marrow (BM) transplantation is of clinical concern particularly involving T-cell-depleted inoculum and transplantations for aplastic anemia. Immune resistance by lymphoid and natural killer (NK) populations with "barrier" function is well established. Major histocompatibility complex (MHC)-identical marrow allografts were examined to investigate effector pathways in non-NK-mediated resistance. Barrier function was examined in cytotoxic normal and deficient B6 (H-2(b)) recipients primed to donor minor histocompatibility antigen (MiHA) prior to BM transplantation. Host resistance was sensitively evaluated by colony-forming unit (CFU) assays to directly assess for donor progenitor cell (PC) and peripheral chimerism. B6 host CD8(+) T cells but not CD4(+) or NK1.1(+) cells effected rejection of primitive (CFU-HPP [high-proliferative potential]) and lineage-committed (CFU-IL3/GM [interleukin 3/granulocyte macrophage]) allogeneic donor progenitors. To address complementation by the cytotoxic pathways existing in singly deficient (perforin or FasL) recipients, cytotoxically double (perforin plus FasL) deficient (cdd) recipients were used. Resistance in B6-cdd recipients was comparable to that of wild-type B6 recipients and was also dependent on CD8(+) T cells. A "triple" cytotoxic deficient model, involving transplantation of TNFR1(-/-) (tumor necrosis factor receptor 1) progenitor grafts did not diminish the ability of B6-cdd recipients to reject allografts. Finally, injection of anti-TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) monoclonal antibody (mAb) in B6-cdd recipients also failed to inhibit rejection of TNFR1(-/-) marrow grafts. In total, these studies demonstrate that CD8(+) host T cells can effectively resist MHC-matched MiHA-mismatched donor PCs via alternative effector pathway(s) independent of perforin-, FasL-, TNFR-1-, and TRAIL-dependent cytotoxicity. Therefore, inhibition of these effector pathways in sensitized recipients is unlikely to result in stem cell engraftment following PC allografts.
authors.affiliation: Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, FL 33101, USA.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Komatsu
authors.forename: Michele
authors.initials: M
authors.lastname: Mammolenti
authors.forename: Monica
authors.initials: M
authors.lastname: Jones
authors.forename: Roland
authors.initials: R
authors.lastname: Jurecic
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Sayers
authors.forename: Robert B
authors.initials: RB
authors.lastname: Levy
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D016026:Bone Marrow Transplantation / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003433:Crosses, Genetic; D017931:DNA Primers; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054353:Perforin; D016133:Polymerase Chain Reaction; D052899:Pore Forming Cytotoxic Proteins; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D053221:TNF-Related Apoptosis-Inducing Ligand; D014184:Transplantation, Homologous / Q000276:immunology; D017211:Treatment Failure; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D019014:fas Receptor / Q000276:immunology
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D017931:DNA Primers; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D054353:Perforin