Murine γ/δ-expressing T cells affect alloengraftment via the recognition of nonclassical major histocompatibility complex class Ib antigens

Abstract

T cells with antidonor specificities have been isolated from human recipients experiencing graft rejection after allogeneic bone marrow transplantation (BMT). Partial T-cell depletion of unrelated BM grafts with an anti-T-cell receptor (TCR) monoclonal antibody (MoAb) directed against the TCR α/β heterodimer have shown that the incidence of graft-versus-host disease is low and that the incidence of durable engraftment is high. These studies suggest either that the number of residual TCR α/β+ cells was sufficient to permit alloengraftment or that the preservation of cells other than TCR α/β+ cells was beneficial for engraftment. With respect to the latter, one such candidate cell is the TCR γ/δ+ T cell. Because no studies have specifically examined whether TCR γ/δ+ cells might be capable of eliminating BM-derived hematopoietic cells, we established a new graft rejection model system in which transgenic (Tg) H-2(d) mice (termed G8), known to express γ/δ heterodimers on a high proportion of peripheral T cells, were used as BMT recipients. These Tg TCR γ/δ+ cells respond vigorously to target cells that express the nonclassical major histocompatibility complex (MHC) class Ib region gene products encoded in H- 2T region of H-2Tb+ strains. G8 Tg mice were used as recipients for C57BL/6 (B6: H-2b; H-2Tb) T-cell-depleted (TCD) donor BM. We show that G8 Tg (H- 2(d), H-2T(d)) mice are potent mediators of B6 BM graft rejection and that the rejection process was inhibited by anti-TCR γ/δ MoAbs. In contrast, BM from a B6 congenic strain that expresses the H-2Ta allele, B6.A-Tlaa/BoyEg, was readily accepted, suggesting that H-2T antigens on repopulating donor BM cells are the targets of host graft rejecting T cells that express the TCR γ/δ heterodimer. PB chimerism studies were performed at ≥1.5 months post- BMT using TCD BM from severe combined immunodeficient allogeneic donors, which is highly susceptible to rejection by the host. The addition of donor G8 TCR γ/δ+ cells to TCD donor BM was shown to significantly increase alloengraftment in B6 recipients. These results show that (1) host TCR γ/δ+ cells can reject repopulating donor cells, presumably by responding to nonclassical MHC class Ib gene products expressed on BM-derived hematopoietic progenitor cells; and (2) donor TCR γ/δ+ cells can facilitate the alloengraftment of rigorously TCD donor BM.