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

Nature Immunology volume 7, pages 401–410 (2006)Cite this article

Abstract

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.

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Acknowledgements

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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Author notes

  1. Chyi-Song Hsieh

    Present address: Department of Medicine and Division of Rheumatology, Washington University, St. Louis, Missouri, 63110, USA

Authors and Affiliations

  1. Department of Medicine and Division of Rheumatology, University of Washington, Seattle, 98195, Washington, USA

    Chyi-Song Hsieh

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

    Ye Zheng, Yuqiong Liang, Jason D Fontenot & Alexander Y Rudensky

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  1. Chyi-Song Hsieh
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Corresponding authors

Correspondence to Chyi-Song Hsieh or Alexander Y Rudensky.

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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). https://doi.org/10.1038/ni1318

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