Donor gamma delta T lymphocytes promote allogeneic engraftment across the major histocompatibility barrier in mice.
T cells that express the alpha beta T-cell receptor are thought to be the T-cell population primarily responsible for facilitating alloengraftment. The role of gamma delta + T cells that comprise only a minority of mature T cells in promoting allogeneic engraftment, however, has not been extensively studied. The purpose of this study was to determine whether gamma delta T cells were capable of facilitating alloengraftment in murine recipients of major histocompatibility complex-mismatched marrow grafts. We developed a model where engraftment of C57BL/6 x 129/F2(H-2b) marrow in sublethally irradiated (800 cGy) recipients (AKR/J, H-2k) is dependent on the presence of mature donor T cells in the marrow graft. In this model, donor T-cell engraftment was significantly augmented by as few as 1 x 10(5) alpha beta T cells. The role of gamma delta T cells was then investigated using transgenic donors (C57BL/6 x 129 background) in which a portion of the T-cell receptor-beta chain gene was deleted by gene targeting so that these mice lack alpha beta T cells. Addition of 10 x 10(5) naive gamma delta T cells to T-cell depleted marrow grafts was required to significantly increase alloengraftment, although donor T cells averaged < 50% of total splenic T cells. To determine whether higher doses of gamma delta T cells would improve donor engraftment and eradicate residual host T cells, gamma delta T cells were ex vivo expanded with a gamma delta T-cell-specific mono-clonal antibody and interleukin-2 and then transplanted into irradiated recipients. Transplantation of > or = 160 x 10(6) activated gamma delta T cells was necessary to consistently and significantly augment donor cell chimerism and enhance hematopoietic reconstitution when compared to control mice, but host T cells persisted in these chimeras. Addition of 2.5 x 10(4) mature alpha beta T cells, which alone were incapable of facilitating engraftment, to T-cell depleted marrow grafts containing 160 x 10(6) activated gamma delta T cells resulted in long-term (> 100 day) complete donor engraftment, indicating that limiting numbers of alpha beta T cells were required in the marrow graft for the eradication of residual host T cells. Using serial weight curves and B-cell reconstitution as end points, clinically significant graft-versus-host disease was not observed in these chimeras under these experimental conditions. These data show that, whereas less potent than alpha beta T cells, gamma delta T cells are able to promote engraftment and enhance hematopoietic reconstitution in allogeneic marrow transplant recipients.
Drobyski
W R
WR
Department of Medicine, Medical College of Wisconsin, Milwaukee, USA.
Majewski
D
D
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D006082:Graft Enhancement, Immunologic / Q000379:methods*; D006084:Graft Rejection / Q000235:genetics / Q000517:prevention & control; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology / Q000517:prevention & control; D006183:H-2 Antigens / Q000235:genetics*; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011828:Radiation Chimera; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000502:physiology*; D013154:Spleen / Q000637:transplantation; D016176:T-Lymphocyte Subsets / Q000378:metabolism / Q000637:transplantation*; D013997:Time Factors; D014019:Tissue Donors; D014184:Transplantation, Homologous
D006183:H-2 Antigens; D016692:Receptors, Antigen, T-Cell, gamma-delta