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An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires


The relationship between the T cell receptor (TCR) repertoires used by self-reactive transcription factor Foxp3–positive (Foxp3+) CD4+ regulatory T cells (Treg cells) and nonregulatory T cells with autoimmune potential is unclear. Here we found that the TCR repertoire of thymic Treg cells in TCRβ-transgenic mice was diverse and was more similar to that of peripheral Treg cells than that of nonregulatory T cells, suggesting that thymic Treg cells make a substantial contribution to the peripheral Treg cell population. Activated T cells in Foxp3-deficient mice, which lack Treg cells, 'preferentially' used TCRs found in the TCR repertoire of Treg cells in Foxp3-sufficient TCRβ-transgenic mice, suggesting that these self-reactive TCRs contribute to the pathology of Foxp3-deficient mice. Our analyses suggest that Treg cells and potentially pathogenic autoimmune T cells use overlapping pools of self-reactive TCRs.

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Figure 1: Sequence similarity between regulatory and nonregulatory TCRs.
Figure 2: Sequence similarity between thymic and peripheral TCRs.
Figure 3: Proliferation induced by regulatory and nonregulatory TCRs.
Figure 4: Function of Foxp3 in thymocytes deletion.
Figure 5: Sequence similarity of CD25+ Foxp3 and CD25+ Foxp3+ TCRs.
Figure 6: Self-reactivity of CD25+ Foxp3 TCRs.


  1. 1

    Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25). J. Immunol. 155, 1151–1164 (1995).

    CAS  PubMed  Google Scholar 

  2. 2

    Powrie, F., Leach, M.W., Mauze, S., Caddle, L.B. & Coffman, R.L. Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation. Int. Immunol. 5, 1461–1471 (1993).

    CAS  Article  Google Scholar 

  3. 3

    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).

    CAS  Article  Google Scholar 

  4. 4

    Maloy, K.J. & Powrie, F. Regulatory T cells in the control of immune pathology. Nat. Immunol. 2, 816–822 (2001).

    CAS  Article  Google Scholar 

  5. 5

    Shevach, E.M. CD4+CD25+ suppressor T cells: more questions than answers. Nat. Rev. Immunol. 2, 389–400 (2002).

    CAS  Article  Google Scholar 

  6. 6

    Taguchi, O. et al. Tissue-specific suppressor T cells involved in self-tolerance are activated extrathymically by self-antigens. Immunology 82, 365–369 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Seddon, B. & Mason, D. Peripheral autoantigen induces regulatory T cells that prevent autoimmunity. J. Exp. Med. 189, 877–882 (1999).

    CAS  Article  Google Scholar 

  8. 8

    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).

    CAS  Article  Google Scholar 

  9. 9

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

    CAS  Article  Google Scholar 

  10. 10

    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).

    CAS  Article  Google Scholar 

  11. 11

    Van Santen, H.-M., Benoist, C. & Mathis, D. Number of T reg cells that differentiate does not increase upon encounter of agonist ligand on thymic epithelial cells. J. Exp. Med. 200, 1221–1230 (2004).

    CAS  Article  Google Scholar 

  12. 12

    Olivares-Villagomez, D., Wang, Y. & Lafaille, J.J. Regulatory CD4+ T cells expressing endogenous T cell receptor chains protect myelin basic protein-specific transgenic mice from spontaneous autoimmune encephalomyelitis. J. Exp. Med. 188, 1883–1894 (1998).

    CAS  Article  Google Scholar 

  13. 13

    Fontenot, J.D. & Rudensky, A.Y. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat. Immunol. 6, 331–337 (2005).

    CAS  Article  Google Scholar 

  14. 14

    Sakaguchi, S. & Sakaguchi, N. Thymus and autoimmunity: capacity of the normal thymus to produce pathogenic self-reactive T cells and conditions required for their induction of autoimmune disease. J. Exp. Med. 172, 537–545 (1990).

    CAS  Article  Google Scholar 

  15. 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).

    CAS  Article  Google Scholar 

  16. 16

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

    CAS  Article  Google Scholar 

  17. 17

    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).

    CAS  Article  Google Scholar 

  18. 18

    Walker, M.R. et al. Induction of Foxp3 and acquisition of T regulatory activity by stimulated human CD4+CD25 T cells. J. Clin. Invest. 112, 1437–1443 (2003).

    CAS  Article  Google Scholar 

  19. 19

    Belkaid, Y., Piccirillo, C.A., Mendez, S., Shevach, E.M. & Sacks, D.L. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420, 502–507 (2002).

    CAS  Article  Google Scholar 

  20. 20

    Yu, W. et al. Continued RAG expression in late stages of B cell development and no apparent re-induction after immunization. Nature 400, 682–687 (1999).

    CAS  Article  Google Scholar 

  21. 21

    Fontenot, J.D. et al. Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity 22, 329–341 (2005).

    CAS  Article  Google Scholar 

  22. 22

    Correia-Neves, M., Waltzinger, C., Mathis, D. & Benoist, C. The shaping of the T cell repertoire. Immunity 14, 21–32 (2001).

    CAS  Article  Google Scholar 

  23. 23

    Klein, L., Khazaie, K. & von Boehmer, H. In vivo dynamics of antigen-specific regulatory T cells not predicted from behavior in vitro. Proc. Natl. Acad. Sci. USA 100, 8886–8891 (2003).

    CAS  Article  Google Scholar 

  24. 24

    Gavin, M.A., Clarke, S.R., Negrou, E., Gallegos, A. & Rudensky, A. Homeostasis and anergy of CD4+CD25+ suppressor T cells in vivo. Nat. Immunol. 3, 33–41 (2002).

    CAS  Article  Google Scholar 

  25. 25

    Chen, Z., Benoist, C. & Mathis, D. How defects in central tolerance impinge on a deficiency in regulatory T cells. Proc. Natl. Acad. Sci. USA 102, 14735–14740 (2005).

    CAS  Article  Google Scholar 

  26. 26

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

    CAS  Article  Google Scholar 

  27. 27

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

    CAS  Article  Google Scholar 

  28. 28

    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).

    CAS  Article  Google Scholar 

  29. 29

    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).

    CAS  Article  Google Scholar 

  30. 30

    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).

    CAS  Article  Google Scholar 

  31. 31

    Itoh, M. et al. Thymus and autoimmunity: Production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J. Immunol. 162, 5317–5326 (1999).

    CAS  PubMed  Google Scholar 

  32. 32

    Fisson, S. et al. Continuous activation of autoreactive CD4+CD25+ regulatory T cells in the steady state. J. Exp. Med. 198, 737–746 (2003).

    CAS  Article  Google Scholar 

  33. 33

    Bhandoola, A. et al. Peripheral expression of self-MHC-II influences the reactivity and self-tolerance of mature CD4+ T cells: evidence from a lymphopenic T cell model. Immunity 17, 425–436 (2002).

    CAS  Article  Google Scholar 

  34. 34

    Wong, P., Goldrath, A.W. & Rudensky, A.Y. Competition for specific intrathymic ligands limits positive selection in a TCR transgenic model of CD4+ T cell development. J. Immunol. 164, 6252–6259 (2000).

    CAS  Article  Google Scholar 

  35. 35

    Mach, N. et al. Differences in dendritic cells stimulated in vivo by tumors engineered to secrete granulocyte-macrophage colony-stimulating factor or Flt3-ligand. Cancer Res. 60, 3239–3246 (2000).

    CAS  PubMed  Google Scholar 

  36. 36

    Magurran, A.E. Ecological diversity and its Measurement 95 (Princeton University Press, Princeton, New Jersey, 1988).

    Book  Google Scholar 

  37. 37

    Colwell, R.K. EstimateS: Statistical estimation of species richness and shared species from samples. Version 6. User's Guide and application (; 1997).

  38. 38

    Casrouge, A. et al. Size estimate of the αβ TCR repertoire of naive mouse splenocytes. J. Immunol. 164, 5782–5787 (2000).

    CAS  Article  Google Scholar 

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We thank K. Forbush for flow cytometry of thymic and peripheral T cells in RAG-GFP mice; M.A. Gavin, L. Williams and J. Kim for discussions and critical reading of the manuscript; and J. Rasmussen, V. Giudicelli (ImMunoGeneTics, Montpellier, France), L. Karpik and M.-W. Liang for technical assistance. Supported by the National Institutes of Health (C.-S.H. and A.Y.R.), the Howard Hughes Medical Institute (A.Y.R.), the Arthritis Foundation–American College of Rheumatology (C.-S.H.) and the Burroughs Wellcome Fund (C.-S.H.).

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Corresponding authors

Correspondence to Chyi-Song Hsieh or Alexander Y Rudensky.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

CDR3 spectratyping of TCRs from Foxp3 and Foxp3+ T cells. (PDF 493 kb)

Supplementary Fig. 2

Phenotypically naive T cells in Foxp3 mice utilize TCRs found in the non-Treg subset in wild-type mice and are typically non-self-reactive. (PDF 617 kb)

Supplementary Table 1

Unique TRAV14 CDR3 sequences in Foxp3+ CD4+ T cell subsets. (PDF 305 kb)

Supplementary Table 2

Unique TRAV14 CDR3 sequences in Foxp3 CD4+ T cell subsets. (PDF 8 kb)

Supplementary Table 3

Analysis of Foxp3gfp Tcra+/− Tcrb-transgenic TRAV14 CDR3 sequences. (PDF 9 kb)

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Hsieh, CS., Zheng, Y., Liang, Y. et al. An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat Immunol 7, 401–410 (2006).

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