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Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice

Nature Immunology volume 8, pages 191–197 (2007)Cite this article

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Abstract

Mice lacking the transcription factor Foxp3 (Foxp3−) lack regulatory T (Treg) cells and develop fatal autoimmune pathology. In Foxp3− mice, many activated effector T cells express self-reactive T cell receptors that are expressed in Treg cells in wild-type mice. Thus, in wild-type mice, most self-reactive thymocytes escaping negative selection are diverted into the Treg lineage, and whether Treg cells are critical in self-tolerance in wild-type mice remains unknown. Here, acute in vivo ablation of Treg cells demonstrated a vital function for Treg cells in neonatal and adult mice. We suggest that self-reactive T cells are continuously suppressed by Treg cells and that when suppression is relieved, self-reactive T cells become activated and facilitate accelerated maturation of dendritic cells.

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Figure 1: Characterization of inducible Treg cell ablation.
Figure 2: Consequences of chronic Treg cell elimination in neonates.
Figure 3: T cell activation in Foxp3− and Foxp3DTR mice depleted of Treg cells from birth.
Figure 4: Consequences of chronic Treg cell elimination in adult mice.
Figure 5: Kinetics of T cell activation in response to acute elimination of Treg cells from adult mice.
Figure 6: Increase in DC numbers after Treg cell elimination.

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Change history

  • 24 December 2006

    In the version of this article initially published online, a name in the first sentence of Acknowledgments is incorrect. The correct name is ‘M. Bevan’. The error has been corrected for all versions of the article.

References

  1. Fontenot, J.D., Gavin, M.A. & Rudensky, A.Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330–336 (2003).

    Article  CAS  Google Scholar 

  2. Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).

    Article  CAS  Google Scholar 

  3. Khattri, R., Cox, T., Yasayko, S.A. & Ramsdell, F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat. Immunol. 4, 337–342 (2003).

    Article  CAS  Google Scholar 

  4. Bennett, C.L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27, 20–21 (2001).

    Article  CAS  Google Scholar 

  5. Brunkow, M.E. et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat. Genet. 27, 68–73 (2001).

    Article  CAS  Google Scholar 

  6. Chatila, T.A. et al. JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J. Clin. Invest. 106, R75–R81 (2000).

    Article  CAS  Google Scholar 

  7. Wildin, R.S. et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat. Genet. 27, 18–20 (2001).

    Article  CAS  Google Scholar 

  8. Kim, J.M. & Rudensky, A. The role of the transcription factor Foxp3 in the development of regulatory T cells. Immunol. Rev. 212, 86–98 (2006).

    Article  CAS  Google Scholar 

  9. Ramsdell, F. Foxp3 and natural regulatory T cells: key to a cell lineage? Immunity 19, 165–168 (2003).

    Article  CAS  Google Scholar 

  10. Sakaguchi, S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu. Rev. Immunol. 22, 531–562 (2004).

    Article  CAS  Google Scholar 

  11. Shevach, E.M. Regulatory T cells in autoimmmunity. Annu. Rev. Immunol. 18, 423–449 (2000).

    Article  CAS  Google Scholar 

  12. Hsieh, C.S. et al. Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity 21, 267–277 (2004).

    Article  CAS  Google Scholar 

  13. Hsieh, C.S., Zheng, Y., Liang, Y., Fontenot, J.D. & Rudensky, A.Y. An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat. Immunol. 7, 401–410 (2006).

    Article  CAS  Google Scholar 

  14. Min, B. et al. Neonates support lymphopenia-induced proliferation. Immunity 18, 131–140 (2003).

    Article  CAS  Google Scholar 

  15. Fontenot, J.D., Dooley, J.L., Farr, A.G. & Rudensky, A.Y. Developmental regulation of Foxp3 expression during ontogeny. J. Exp. Med. 202, 901–906 (2005).

    Article  CAS  Google Scholar 

  16. Bogue, M., Gilfillan, S., Benoist, C. & Mathis, D. Regulation of N-region diversity in antigen receptors through thymocyte differentiation and thymus ontogeny. Proc. Natl. Acad. Sci. USA 89, 11011–11015 (1992).

    Article  CAS  Google Scholar 

  17. Gavin, M.A. & Bevan, M.J. Increased peptide promiscuity provides a rationale for the lack of N regions in the neonatal T cell repertoire. Immunity 3, 793–800 (1995).

    Article  CAS  Google Scholar 

  18. Jonuleit, H. et al. Infectious tolerance: human CD25+ regulatory T cells convey suppressor activity to conventional CD4+ T helper cells. J. Exp. Med. 196, 255–260 (2002).

    Article  CAS  Google Scholar 

  19. Waldmann, H. & Cobbold, S. Regulating the immune response to transplants. a role for CD4+ regulatory cells? Immunity 14, 399–406 (2001).

    Article  CAS  Google Scholar 

  20. Buch, T. et al. A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration. Nat Methods 2, 419–426 (2005).

    Article  CAS  Google Scholar 

  21. Russell, W.L., Russell, L.B. & Gower, J.S. Exceptional inheritance of a sex-linked gene in the mouse explained on the basis that the X/O sex-chromosome constitution is female. Proc. Natl. Acad. Sci. USA 45, 554–560 (1959).

    Article  CAS  Google Scholar 

  22. Kamath, A.T. et al. The development, maturation, and turnover rate of mouse spleen dendritic cell populations. J. Immunol. 165, 6762–6770 (2000).

    Article  CAS  Google Scholar 

  23. Cederbom, L., Hall, H. & Ivars, F. CD4+CD25+ regulatory T cells down-regulate co-stimulatory molecules on antigen-presenting cells. Eur. J. Immunol. 30, 1538–1543 (2000).

    Article  CAS  Google Scholar 

  24. Houot, R., Perrot, I., Garcia, E., Durand, I. & Lebecque, S. Human CD4+CD25high regulatory T cells modulate myeloid but not plasmacytoid dendritic cells activation. J. Immunol. 176, 5293–5298 (2006).

    Article  CAS  Google Scholar 

  25. Misra, N., Bayry, J., Lacroix-Desmazes, S., Kazatchkine, M.D. & Kaveri, S.V. Cutting edge: human CD4+CD25+ T cells restrain the maturation and antigen-presenting function of dendritic cells. J. Immunol. 172, 4676–4680 (2004).

    Article  CAS  Google Scholar 

  26. Veldhoen, M., Moncrieffe, H., Hocking, R.J., Atkins, C.J. & Stockinger, B. Modulation of dendritic cell function by naive and regulatory CD4+ T cells. J. Immunol. 176, 6202–6210 (2006).

    Article  CAS  Google Scholar 

  27. Apostolou, I., Sarukhan, A., Klein, L. & von Boehmer, H. Origin of regulatory T cells with known specificity for antigen. Nat. Immunol. 3, 756–763 (2002).

    Article  CAS  Google Scholar 

  28. Jordan, M.S. et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat. Immunol. 2, 301–306 (2001).

    Article  CAS  Google Scholar 

  29. Kawahata, K. et al. Generation of CD4+CD25+ regulatory T cells from autoreactive T cells simultaneously with their negative selection in the thymus and from nonautoreactive T cells by endogenous TCR expression. J. Immunol. 168, 4399–4405 (2002).

    Article  CAS  Google Scholar 

  30. Walker, L.S., Chodos, A., Eggena, M., Dooms, H. & Abbas, A.K. Antigen-dependent proliferation of CD4+ CD25+ regulatory T cells in vivo. J. Exp. Med. 198, 249–258 (2003).

    Article  CAS  Google Scholar 

  31. Chen, Y., Kuchroo, V.K., Inobe, J., Hafler, D.A. & Weiner, H.L. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 265, 1237–1240 (1994).

    Article  CAS  Google Scholar 

  32. Groux, H. et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–742 (1997).

    Article  CAS  Google Scholar 

  33. Foussat, A. et al. A comparative study between T regulatory type 1 and CD4+CD25+ T cells in the control of inflammation. J. Immunol. 171, 5018–5026 (2003).

    Article  CAS  Google Scholar 

  34. Asano, M., Toda, M., Sakaguchi, N. & Sakaguchi, S. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J. Exp. Med. 184, 387–396 (1996).

    Article  CAS  Google Scholar 

  35. Nishizuka, Y. & Sakakura, T. Thymus and reproduction: sex-linked dysgenesia of the gonad after neonatal thymectomy in mice. Science 166, 753–755 (1969).

    Article  CAS  Google Scholar 

  36. Apostolou, I. & von Boehmer, H. In vivo instruction of suppressor commitment in naive T cells. J. Exp. Med. 199, 1401–1408 (2004).

    Article  CAS  Google Scholar 

  37. Chen, W. et al. Conversion of peripheral CD4+CD25− naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J. Exp. Med. 198, 1875–1886 (2003).

    Article  CAS  Google Scholar 

  38. Thorstenson, K.M. & Khoruts, A. Generation of anergic and potentially immunoregulatory CD25+CD4 T cells in vivo after induction of peripheral tolerance with intravenous or oral antigen. J. Immunol. 167, 188–195 (2001).

    Article  CAS  Google Scholar 

  39. von Boehmer, H. Mechanisms of suppression by suppressor T cells. Nat. Immunol. 6, 338–344 (2005).

    Article  CAS  Google Scholar 

  40. Grossman, W.J. et al. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 21, 589–601 (2004).

    Article  CAS  Google Scholar 

  41. Tadokoro, C.E. et al. Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo. J. Exp. Med. 203, 505–511 (2006).

    Article  CAS  Google Scholar 

  42. Tang, Q. et al. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat. Immunol. 7, 83–92 (2006).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank D. Liggit for assistance with the analysis of histopathology; A. Gall, L. Karpik, T. Chu, K. Forbush, P. deRoos and M. Schwartz for assistance; R. Setoguchi and M. Bevan (University of Washington) for SMARTA Rag2−/− mice; and members of the Rudensky lab for discussions. The CD11c-DTR-GFP plasmid was a gift from R. Lang (Children's Hospital, Cincinnati, Ohio). Suported by the Howard Hughes Medical Institute (A.Y.R.), Cancer Research Institute (J.M.K.) and US National Institutes of Health (A.Y.R.).

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Authors and Affiliations

  1. Department of Immunology, University of Washington, Seattle, 98195, Washington, USA

    Jeong M Kim, Jeffrey P Rasmussen & Alexander Y Rudensky

  2. Howard Hughes Medical Institute, University of Washington, Seattle, 98195, Washington, USA

    Alexander Y Rudensky

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  1. Jeong M Kim
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Correspondence to Alexander Y Rudensky.

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Supplementary information

Supplementary Fig. 1

Generation of the Foxp3DTR knockin allele. (PDF 827 kb)

Supplementary Fig. 2

Increased generation of myeloid dendritic cells in response to Treg cell elimination. (PDF 225 kb)

Supplementary Fig. 3

Increased expression of CD40L, RANKL, GM-CSF, IL-3 by CD4+ Foxp3− T cells after Treg cell elimination. (PDF 328 kb)

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Kim, J., Rasmussen, J. & Rudensky, A. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol 8, 191–197 (2007). https://doi.org/10.1038/ni1428

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