Mast cells are essential intermediaries in regulatory T-cell tolerance

Li-Fan Lu, Evan F. Lind, David C. Gondek, Kathy A. Bennett, Michael W. Gleeson, Karina Pino-Lagos, Zachary A. Scott, Anthony J. Coyle, Jennifer L. Reed, Jacques Van Snick, Terry B. Strom, Xin Xiao Zheng and Randolph J. Noelle ()
Additional contact information
Li-Fan Lu: Dartmouth Medical School and the Norris Cotton Cancer Center
Evan F. Lind: Dartmouth Medical School and the Norris Cotton Cancer Center
David C. Gondek: Dartmouth Medical School and the Norris Cotton Cancer Center
Kathy A. Bennett: Dartmouth Medical School and the Norris Cotton Cancer Center
Michael W. Gleeson: Dartmouth Medical School and the Norris Cotton Cancer Center
Karina Pino-Lagos: Dartmouth Medical School and the Norris Cotton Cancer Center
Zachary A. Scott: Dartmouth Medical School and the Norris Cotton Cancer Center
Anthony J. Coyle: MedImmune
Jennifer L. Reed: MedImmune
Jacques Van Snick: Université de Louvain, Brussels Branch
Terry B. Strom: Beth Israel Deaconess Medical Center, Harvard Medical School
Xin Xiao Zheng: Beth Israel Deaconess Medical Center, Harvard Medical School
Randolph J. Noelle: Dartmouth Medical School and the Norris Cotton Cancer Center

Nature, 2006, vol. 442, issue 7106, 997-1002

Abstract: Abstract Contrary to the proinflammatory role of mast cells in allergic disorders, the results obtained in this study establish that mast cells are essential in CD4+CD25+Foxp3+ regulatory T (TReg)-cell-dependent peripheral tolerance. Here we confirm that tolerant allografts, which are sustained owing to the immunosuppressive effects of TReg cells, acquire a unique genetic signature dominated by the expression of mast-cell-gene products. We also show that mast cells are crucial for allograft tolerance, through the inability to induce tolerance in mast-cell-deficient mice. High levels of interleukin (IL)-9—a mast cell growth and activation factor—are produced by activated TReg cells, and IL-9 production seems important in mast cell recruitment to, and activation in, tolerant tissue. Our data indicate that IL-9 represents the functional link through which activated TReg cells recruit and activate mast cells to mediate regional immune suppression, because neutralization of IL-9 greatly accelerates allograft rejection in tolerant mice. Finally, immunohistochemical analysis clearly demonstrates the existence of this novel TReg–IL-9–mast cell relationship within tolerant allografts.

Date: 2006
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DOI: 10.1038/nature05010

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