Both γδ T cells and NK cells inhibit the engraftment of xenogeneic rat bone marrow cells and the induction of xenograft tolerance in mice

In murine allogeneic bone marrow transplantation recipients, treatment of the hosts with a nonmyeloablative regimen, including depleting anti-CD4 and anti-CD8 mAbs, allows establishment of long-term mixed chimerism and donor-specific tolerance. However, in the xenogeneic rat-to-mouse combination, additional anti-Thy1.2 and anti-NK1.1 mAbs are required. We have now attempted to identify the xenoresistant mouse cell populations that are targeted by anti-NK1.1 and anti-Thy1.2 mAbs. C57BL/6 (B6) wild-type, B6 TCRβ^-/-, and B6 TCRδ^-/- mice received anti-CD4 and anti-CD8 mAbs, followed by 3 Gy of whole body irradiation, 7 Gy of thymic irradiation, and transplantation of T cell-depleted rat bone marrow cells. Anti-NK1.1 and anti-Thy1.2 mAbs were additionally administered to some groups. Increased rat chimerism was observed in TCRδ^-/- mice treated with anti-CD4, anti-CD8, and anti-NK1.1 mAbs compared with similarly treated TCRβ^-/- mice. In TCRβ^-/- mice, but not in TCR δ^-/- mice, donor chimerism was increased by treatment with anti-Thy1.2 mAb, indicating that CD4^-CD8^-TCRγδ⁺Thy1.2⁺ NK1.1^- cells (γδ T cells) are involved in the rejection of rat marrow. In addition, chimerism was enhanced in both TCRβ^-/- and TCRδ^-/- mice treated with anti-CD4, anti-CD8, and anti-Thy1.2 mAbs by the addition of anti-NK1.1 mAb to the conditioning regimen. Donor-specific skin graft prolongation was enhanced by anti-Thy1.2 and anti-NK1.1 mAbs in TCRδ^-/- mice. Therefore, in addition to CD4 and CD8 T cells, γδ T cells and NK cells play a role in resisting engraftment of rat marrow and the induction of xenograft tolerance in mice.