1. Department of Microbiology & Immunology, Dartmouth Medical School and the Norris Cotton Cancer Center, 1 Medical Center Drive, Lebanon, New Hampshire 03756, USA
2. Department of Autoimmunity and Inflammation, MedImmune, Gaithersburg, Maryland 20878, USA
3. Ludwig Institute for Cancer Research (Brussels Branch) and Experimental Medicine Unit, Université de Louvain, Brussels Branch, 74 Avenue Hippocrate, UCL 7459, B-1200 Brussels, Belgium
4. Department of Medicine, Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA

Correspondence to: Randolph J. Noelle¹ Correspondence and requests for materials should be addressed to R.J.N. (Email: rjn@dartmouth.edu).

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 (T_Reg)-cell-dependent peripheral tolerance. Here we confirm that tolerant allografts, which are sustained owing to the immunosuppressive effects of T_Reg 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 T_Reg 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 T_Reg 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 T_Reg–IL-9–mast cell relationship within tolerant allografts.

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