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.
Barao
Isabel
I
Department of Microbiology and Immunology, University of Nevada School of Medicine, Reno, NV 89557, USA.
Hanash
Alan M
AM
Hallett
William
W
Welniak
Lisbeth A
LA
Sun
Kai
K
Redelman
Doug
D
Blazar
Bruce R
BR
Levy
Robert B
RB
Murphy
William J
WJ
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