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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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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.

References

  1. 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)

    Article  CAS  Google Scholar 

  2. 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)

    Article  CAS  Google Scholar 

  3. 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)

    Article  CAS  Google Scholar 

  4. Galli, S. J., Nakae, S. & Tsai, M. Mast cells in the development of adaptive immune responses. Nature Immunol. 6, 135–142 (2005)

    Article  CAS  Google Scholar 

  5. Galli, S. J. et al. Mast cells as “tunable” effector and immunoregulatory cells: recent advances. Annu. Rev. Immunol. 23, 749–786 (2005)

    Article  CAS  Google Scholar 

  6. Benoist, C. & Mathis, D. Mast cells in autoimmune disease. Nature 420, 875–878 (2002)

    Article  ADS  CAS  Google Scholar 

  7. Zelenika, D. et al. The role of CD4+ T-cell subsets in determining transplantation rejection or tolerance. Immunol. Rev. 182, 164–179 (2001)

    Article  CAS  Google Scholar 

  8. Graca, L., Cobbold, S. P. & Waldmann, H. Identification of regulatory T cells in tolerated allografts. J. Exp. Med. 195, 1641–1646 (2002)

    Article  CAS  Google Scholar 

  9. 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)

    Article  CAS  Google Scholar 

  10. 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)

    Article  CAS  Google Scholar 

  11. 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)

    Article  CAS  Google Scholar 

  12. 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)

    CAS  PubMed  Google Scholar 

  13. 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)

    CAS  PubMed  Google Scholar 

  14. 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)

    Article  CAS  Google Scholar 

  15. 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)

    Article  CAS  Google Scholar 

  16. Jarnicki, A. G. & Fallon, P. G. T helper type-2 cytokine responses: potential therapeutic targets. Curr. Opin. Pharmacol. 3, 449–455 (2003)

    Article  CAS  Google Scholar 

  17. 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)

    Article  CAS  Google Scholar 

  18. 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)

    Article  CAS  Google Scholar 

  19. 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)

    Article  CAS  Google Scholar 

  20. 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)

    Article  ADS  CAS  Google Scholar 

  21. 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)

    Article  CAS  Google Scholar 

  22. 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)

    Article  CAS  Google Scholar 

  23. Theoharides, T. C. & Conti, P. Mast cells: the Jekyll and Hyde of tumor growth. Trends Immunol. 25, 235–241 (2004)

    Article  CAS  Google Scholar 

  24. 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)

    Article  CAS  Google Scholar 

  25. Lee, G. K. & Mellor, A. L. Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division. Immunology 107, 452–460 (2002)

    Article  CAS  Google Scholar 

  26. 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)

    Article  CAS  Google Scholar 

  27. 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)

    Article  CAS  Google Scholar 

  28. 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)

    Article  CAS  Google Scholar 

  29. Saitoh, S. et al. LAT is essential for FcɛRI-mediated mast cell activation. Immunity 12, 525–535 (2000)

    Article  CAS  Google Scholar 

  30. 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)

    Article  CAS  Google Scholar 

Download references

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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Lu, LF., Lind, E., Gondek, D. et al. Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature 442, 997–1002 (2006). https://doi.org/10.1038/nature05010

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