Suppression of natural killer cell-mediated bone marrow cell rejection by CD4+CD25+ regulatory T cells
- Isabel Barao*,
- Alan M. Hanash†,
- William Hallett*,
- Lisbeth A. Welniak*,
- Kai Sun*,
- Doug Redelman‡,
- Bruce R. Blazar§,
- Robert B. Levy†,¶, and
- William J. Murphy*,¶,‖
- Departments of *Microbiology and Immunology and
- ‡Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557;
- †Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33101; and
- §Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN 55455
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Edited by Shimon Sakaguchi, Kyoto University, Kyoto, Japan, and accepted by the Editorial Board February 10, 2006
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↵ ¶R.B.L. and W.J.M. contributed equally to this work. (received for review October 23, 2005)
Abstract
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.
Footnotes
- ‖To whom correspondence should be addressed. E-mail: wmurphy{at}unr.edu
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Author contributions: I.B., L.A.W., D.R., B.R.B., R.B.L., and W.J.M. designed research; I.B., A.M.H., W.H., K.S., and D.R. performed research; B.R.B. contributed new reagents/analytic tools; I.B., A.M.H., W.H., L.A.W., K.S., and D.R. analyzed data; and I.B. and W.J.M. wrote the paper.
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Conflict of interest statement: No conflicts declared.
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S.S. is a guest editor invited by the Editorial Board.
- Abbreviations:
- BM,
- bone marrow;
- BMC,
- BM cell;
- BMT,
- BM transplantation;
- CFU-GM,
- colony-forming unit–granulocyte/monocyte;
- Treg,
- T regulatory;
- NK,
- natural killer;
- poly(I:C),
- polyinosinic:polycytidylic acid;
- TBI,
- total body irradiation.
Abbreviations:
- © 2006 by The National Academy of Sciences of the USA
