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

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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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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Competing interests

The authors declare no competing financial interests.

Correspondence to Chyi-Song Hsieh or Alexander Y Rudensky.

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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Further reading

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.