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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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.).
The authors declare no competing financial interests.
CDR3 spectratyping of TCRs from Foxp3− and Foxp3+ T cells. (PDF 493 kb)
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)
Unique TRAV14 CDR3 sequences in Foxp3+ CD4+ T cell subsets. (PDF 305 kb)
Unique TRAV14 CDR3 sequences in Foxp3− CD4+ T cell subsets. (PDF 8 kb)
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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