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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Sakaguchi, S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nature Immunol. 6, 345–352 (2005)
Quezada, S. A. et al. Analysis of the underlying cellular mechanisms of anti-CD154-induced graft tolerance: the interplay of clonal anergy and immune regulation. J. Immunol. 175, 771–779 (2005)
Taylor, P. A., Noelle, R. J. & Blazar, B. R. CD4+CD25+ immune regulatory cells are required for induction of tolerance to alloantigen via costimulatory blockade. J. Exp. Med. 193, 1311–1318 (2001)
Galli, S. J., Nakae, S. & Tsai, M. Mast cells in the development of adaptive immune responses. Nature Immunol. 6, 135–142 (2005)
Galli, S. J. et al. Mast cells as “tunable” effector and immunoregulatory cells: recent advances. Annu. Rev. Immunol. 23, 749–786 (2005)
Benoist, C. & Mathis, D. Mast cells in autoimmune disease. Nature 420, 875–878 (2002)
Zelenika, D. et al. The role of CD4+ T-cell subsets in determining transplantation rejection or tolerance. Immunol. Rev. 182, 164–179 (2001)
Graca, L., Cobbold, S. P. & Waldmann, H. Identification of regulatory T cells in tolerated allografts. J. Exp. Med. 195, 1641–1646 (2002)
Hara, M. et al. IL-10 is required for regulatory T cells to mediate tolerance to alloantigens in vivo. J. Immunol. 166, 3789–3796 (2001)
Corti, B. et al. Potential of real-time PCR assessment of granzyme B and perforin up-regulation for rejection monitoring in intestinal transplant recipients. Transplant. Proc. 37, 4467–4471 (2005)
Wang, H. W., Tedla, N., Lloyd, A. R., Wakefield, D. & McNeil, P. H. Mast cell activation and migration to lymph nodes during induction of an immune response in mice. J. Clin. Invest. 102, 1617–1626 (1998)
Berrozpe, G. et al. The Wsh, W57, and Ph Kit expression mutations define tissue-specific control elements located between -23 and -154 kb upstream of Kit. Blood 94, 2658–2666 (1999)
Yamazaki, M. et al. C-kit gene is expressed by skin mast cells in embryos but not in puppies of Wsh/Wsh mice: age-dependent abolishment of c-kit gene expression. Blood 83, 3509–3516 (1994)
Grimbaldeston, M. A. et al. Mast cell-deficient W-sash c-kit mutant KitW-sh/W-sh mice as a model for investigating mast cell biology in vivo. Am. J. Pathol. 167, 835–848 (2005)
Van Snick, J. et al. Cloning and characterization of a cDNA for a new mouse T cell growth factor (P40). J. Exp. Med. 169, 363–368 (1989)
Jarnicki, A. G. & Fallon, P. G. T helper type-2 cytokine responses: potential therapeutic targets. Curr. Opin. Pharmacol. 3, 449–455 (2003)
Zhou, Y., McLane, M. & Levitt, R. C. Th2 cytokines and asthma. Interleukin-9 as a therapeutic target for asthma. Respir. Res. 2, 80–84 (2001)
Townsend, J. M. et al. IL-9-deficient mice establish fundamental roles for IL-9 in pulmonary mastocytosis and goblet cell hyperplasia but not T-cell development. Immunity 13, 573–583 (2000)
Shimizu, J., Yamazaki, S., Takahashi, T., Ishida, Y. & Sakaguchi, S. Stimulation of CD25+CD4+ regulatory T cells through GITR breaks immunological self-tolerance. Nature Immunol. 3, 135–142 (2002)
Tone, M. et al. Mouse glucocorticoid-induced tumor necrosis factor receptor ligand is costimulatory for T cells. Proc. Natl Acad. Sci. USA 100, 15059–15064 (2003)
Chen, W. et al. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J. Exp. Med. 198, 1875–1886 (2003)
Jarvinen, L. Z., Blazar, B. R., Adeyi, O. A., Strom, T. B. & Noelle, R. J. CD154 on the surface of CD4+CD25+ regulatory T cells contributes to skin transplant tolerance. Transplantation 76, 1375–1379 (2003)
Theoharides, T. C. & Conti, P. Mast cells: the Jekyll and Hyde of tumor growth. Trends Immunol. 25, 235–241 (2004)
Mesples, B., Fontaine, R. H., Lelievre, V., Launay, J. M. & Gressens, P. Neuronal TGF-β1 mediates IL-9/mast cell interaction and exacerbates excitotoxicity in newborn mice. Neurobiol. Dis. 18, 193–205 (2005)
Lee, G. K. & Mellor, A. L. Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division. Immunology 107, 452–460 (2002)
Wedemeyer, J. & Galli, S. J. Decreased susceptibility of mast cell-deficient KitW/KitW-v mice to the development of 1,2-dimethylhydrazine-induced intestinal tumors. Lab. Invest. 85, 388–396 (2005)
Khan, W. I. et al. Modulation of intestinal muscle contraction by interleukin-9 (IL-9) or IL-9 neutralization: correlation with worm expulsion in murine nematode infections. Infect. Immun. 71, 2430–2438 (2003)
Razin, E. Culture of bone marrow-derived mast cells: a model for studying oxidative metabolism of arachidonic acid and synthesis of other molecules derived from membrane phospholipids. Methods Enzymol. 187, 514–520 (1990)
Saitoh, S. et al. LAT is essential for FcɛRI-mediated mast cell activation. Immunity 12, 525–535 (2000)
Gondek, D. C., Lu, L. F., Quezada, S. A., Sakaguchi, S. & Noelle, R. J. Cutting edge: contact-mediated suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism. J. Immunol. 174, 1783–1786 (2005)
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.
Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.
Granzyme B and Perforin expression in allografts. (JPG 14 kb)
Bone marrow derived-mast cells (BMMCs) reconstitution (JPG 32 kb)
The effect of IL-9 on Treg activities. (JPG 31 kb)
IL-9 production in situ. (JPG 65 kb)
Mast cell numbers in Rag-/- mice after αIL-9 administration. (JPG 19 kb)
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)
This file contains text to accompany the above Supplementary Figures. (DOC 32 kb)
About this article
American Journal of Transplantation (2019)
An Update on Interleukin-9: From Its Cellular Source and Signal Transduction to Its Role in Immunopathogenesis
International Journal of Molecular Sciences (2019)
Immunology Letters (2019)
Type 2 Inflammatory Responses in Autoimmune Demyelination of the Central Nervous System: Recent Advances
Journal of Immunology Research (2019)