DONOR GAMMA-DELTA T-LYMPHOCYTES PROMOTE ALLOGENEIC ENGRAFTMENT ACROSSTHE 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 alloengra ftment. The role of gamma delta(+) T cells that comprise only a minori ty of mature T cells in promoting allogeneic engraftment, however, has not been extensively studied. The purpose of this study was to determ ine whether gamma delta T cells were capable of facilitating alloengra ftment in murine recipients of major histocompatibility complex-mismat ched marrow grafts. We developed a model where engraftment of C57BL/6 x 129/F2 (H-2(b)) marrow in sublethally irradiated (800 cGy) recipient s (AKR/J, H-2(k)) is dependent on the presence of mature donor T cells in the marrow graft. In this model, donor T-cell engraftment was sign ificantly augmented by as few as 1 x 10(5) cup T cells. The role of ga mma delta T cells was then investigated using transgenic donors (C57BL /6 x 129 background) in which a portion of the T-cell receptor-beta ch ain gene was deleted by gene targeting so that these mice lack alpha b eta T cells. Addition of 10 x 10(6) naive gamma delta T cells to T-cel l depleted marrow grafts was required to significantly increase alloen graftment, although donor T cells averaged <50% of total splenic T cel ls. To determine whether higher doses of gamma delta T cells would imp rove donor engraftment and eradicate residual host T cells, gamma delt a T cells were ex vivo expanded with a gamma delta T-cell-specific mon oclonal antibody and interleukin-2 and then transplanted into irradiat ed recipients. Transplantation of greater than or equal to 160 x 10(6) activated gamma delta T cells was necessary to consistently and signi ficantly augment donor cell chimerism and enhance hematopoietic recons titution 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, whi ch alone were incapable of facilitating engraftment, to T-cell deplete d marrow grafts containing 160 x 10(8) activated gamma delta T cells r esulted in long-term (>100 day) complete donor engraftment, indicating that limiting numbers of alpha beta T cells were required in the marr ow graft for the eradication of residual host T cells. Using serial we ight curves and B-cell reconstitution as end points, clinically signif icant graft-versus-host disease was not observed in these chimeras und er these experimental conditions. These data show that, whereas less p otent than alpha beta T cells, gamma delta T cells are able to promote engraftment and enhance hematopoietic reconstitution in allogeneic ma rrow transplant recipients. (C) 1997 by The American Society of Hemato logy.