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 x C57BL/6) F(1) 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-beta mAb treatment also increased NK cell-mediated BM graft rejection, suggesting that the NK cell suppression is exerted through TGF-beta. 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.
Department of Microbiology and Immunology, University of Nevada School of Medicine, Reno, NV 89557, USA.
Isabel
I
Barao
Alan M
AM
Hanash
William
W
Hallett
Lisbeth A
LA
Welniak
Kai
K
Sun
Doug
D
Redelman
Bruce R
BR
Blazar
Robert B
RB
Levy
William J
WJ
Murphy
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology*; D016026:Bone Marrow Transplantation; D015704:CD4 Antigens / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009500:Neutralization Tests; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D015704:CD4 Antigens; D015375:Receptors, Interleukin-2