Suppression of natural killer cell-mediated bone marrow cell rejection by CD4⁺CD25⁺ regulatory T cells

Naturally occurring CD4⁺CD25⁺ T regulatory (Treg) cells have been shown to inhibit adaptive responses by T cells. Natural killer (NK) cells represent an important component of innate immunity in both cancer and infectious disease states. We investigated whether CD4⁺CD25 ⁺ Treg cells could affect NK cell function in vivo by using allogeneic (full H2-disparate) bone marrow (BM) transplantation and the model of hybrid resistance, in which parental marrow grafts are rejected solely by the NK cells of irradiated (BALB/c × C57BL/6) F₁ recipients. We demonstrate that the prior removal of host Treg cells, but not CD8⁺ T cells, significantly enhanced NK cell-mediated BM rejection in both models. The inhibitory role of Treg cells on NK cells was confirmed in vivo with adoptive transfer studies in which transferred CD4⁺CD25⁺ cells could abrogate NK cell-mediated hybrid resistance. Anti-TGF-β mAb treatment also increased NK cell-mediated BM graft rejection, suggesting that the NK cell suppression is exerted through TGF-β. Thus, CD4⁺CD25 ⁺ Treg cells can potently inhibit NK cell function in vivo, and their depletion may have therapeutic ramifications for NK cell function in BM transplantation and cancer therapy.