CD4 T cell-mediated alloresistance to fully MHC-mismatched allogeneic bone marrow engraftment is dependent on CD40-CD40 ligand interactions, and lasting T cell tolerance is induced by bone marrow transplantation with initial blockade of this pathway.
Costimulatory blockade can be used to promote allogeneic marrow engraftment and tolerance induction, but on its own is not 100% reliable. We sought to determine whether one or the other of the CD4 or CD8 T cell subsets of the recipient was primarily responsible for resistance to allogeneic marrow engraftment in mice receiving costimulatory blockade, and to use this information to develop a more reliable, minimal conditioning regimen for induction of mixed chimerism and transplantation tolerance. We demonstrate that a single anti-CD40 ligand mAb treatment is sufficient to completely overcome CD4 cell-mediated resistance to allogeneic marrow engraftment and rapidly induce CD4 cell tolerance, but does not reliably overcome CD8 CTL-mediated alloresistance. The data suggest that costimulation, which activates alloreactive CTL, is insufficient to activate alloreactive CD4 cells when the CD40 pathway is blocked. The addition of host CD8 T cell depletion to anti-CD40 ligand treatment reliably allows the induction of mixed chimerism and donor-specific skin graft tolerance in 3 Gy-irradiated mice receiving fully MHC-mismatched bone marrow grafts. Thus, despite the existence of multiple costimulatory pathways and pathways of APC activation, our studies demonstrate an absolute dependence on CD40-mediated events for CD4 cell-mediated rejection of allogeneic marrow. Exposure to donor bone marrow allows rapid tolerization of alloreactive CD4 cells when the CD40 pathway is blocked, leading to permanent marrow engraftment and intrathymic tolerization of T cells that develop subsequently.
Ito
H
H
Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital, Boston, MA 02129, USA.
Kurtz
J
J
Shaffer
J
J
Sykes
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D016026:Bone Marrow Transplantation / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000528:radiation effects; D019013:CD40 Antigens / Q000276:immunology / Q000502:physiology*; D023201:CD40 Ligand / Q000276:immunology / Q000502:physiology*; D016827:CD8 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000528:radiation effects; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology / Q000528:radiation effects; D017637:Clonal Deletion / Q000235:genetics / Q000528:radiation effects; D004306:Dose-Response Relationship, Immunologic; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006650:Histocompatibility Testing; D007274:Injections, Intraperitoneal; D008212:Lymphocyte Depletion; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011828:Radiation Chimera / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology* / Q000528:radiation effects; D019172:Transplantation Conditioning; D023001:Transplantation Tolerance / Q000235:genetics* / Q000528:radiation effects; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D019013:CD40 Antigens; D016827:CD8 Antigens; D023201:CD40 Ligand