Co-stimulated/Tc2 cells abrogate murine marrow graft rejection.
CD3/CD28 co-stimulation activates T-cell cytokine and cytolytic effector function and therefore represents an approach to modulate donor T cells before allogeneic bone marrow transplantation (BMT). We hypothesized that co-stimulation of donor T cells under T2 conditions would generate CD4+ T-helper type 2 (Th2) and CD8+ Tc2 cells capable of abrogating marrow graft rejection with reduced graft-versus-host disease (GVHD). Relative to control co-stimulated Th1/Tc1 (T1) cells, co-stimulated T2 cells secreted reduced interleukin (IL)-2 and interferon-gamma and increased IL-4 and IL-10, expressed reduced fas ligand, and had similar total cytolytic capacity. In an F1-into-parent sublethal irradiation model, T2 cells potently abrogated rejection; this veto effect was partially attenuated if T2 cell infusion was delayed for 24 hours after BMT. Cell-tracking studies determined that T2 cells were quantitatively reduced after BMT when administered to hosts capable of mounting a host-versus-graft rejection response; both donor and host cytotoxic T lymphocytes may therefore have been deleted during Th2/Tc2 cell facilitation of engraftment. Donor T2 cells also abrogated rejection in an F1-into-parent model that used lethal host irradiation and subsequent host T-cell addback. Further experiments in a P1-into-P2 transplantation model demonstrated that donor T2 cells abrogated rejection with reduced GVHD in a transplant setting involving full major histocompatibility complex disparity in both the host-versus-graft and graft-versus-host directions. The capacity of T2 cells to abrogate rejection with reduced GVHD was a function of both the number of T2 cells infused and the number of T cells present after host preparation. Co-stimulation under T2 polarizing conditions therefore rapidly generates donor Th2/Tc2 cells that potently abrogate murine marrow rejection with reduced GVHD.
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Andreas A
AA
Erdmann
Unsu
U
Jung
Jason E
JE
Foley
Yoko
Y
Toda
Daniel H
DH
Fowler
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D003433:Crosses, Genetic; D005260:Female; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology*; D007165:Immunosuppression Therapy / Q000379:methods; D007371:Interferon-gamma / Q000276:immunology; D007378:Interleukins / Q000276:immunology; D017710:Lymphocyte Transfusion; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014916:Whole-Body Irradiation
D007378:Interleukins; D007371:Interferon-gamma