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 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.
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Acknowledgements We thank S. Galli for critical review of the manuscript during preparation. This work was supported by NIH grants; J.V.S.’s research was funded in part by the Belgian Federal Service for Scientific, Technical and Cultural Affairs and by the Actions de Recherche Concertées, Communauté franc¸aise de Belgique, Direction de la recherché scientifique.