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Mast cells are essential intermediaries in regulatory T-cell tolerance

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.

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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 française de Belgique, Direction de la recherché scientifique.

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Correspondence to Randolph J. Noelle.

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Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Supplementary information

Supplementary Figure 1

Granzyme B and Perforin expression in allografts. (JPG 14 kb)

Supplementary Figure 2

Bone marrow derived-mast cells (BMMCs) reconstitution (JPG 32 kb)

Supplementary Figure 3

The effect of IL-9 on Treg activities. (JPG 31 kb)

Supplementary Figure 4

IL-9 production in situ. (JPG 65 kb)

Supplementary Figure 5

Mast cell numbers in Rag-/- mice after αIL-9 administration. (JPG 19 kb)

Supplementary Tables

Supplementary Table 1 details the numbers of mast cells in LN post-grafting. Supplementary Table 2 details numbers of regulatory T cells in skin post-grafting. (DOC 43 kb)

Supplementary Figure Legends

This file contains text to accompany the above Supplementary Figures. (DOC 32 kb)

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Further reading

Figure 1: Mast-cell-related gene expression in tolerant allografts.
Figure 2: Histological analysis of cell infiltration in tolerant allografts.
Figure 3: Mast-cell-deficient mice are not capable of establishing long-term allograft tolerance.
Figure 4: TReg cells produce high levels of IL-9 on activation both in vitro and in vivo.
Figure 5: IL-9 secreted by T Reg cell functionally links mast cells to T Reg -cell-mediated allograft tolerance.

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