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Section on Immunology and Immunogenetics, Joslin Diabetes Center and Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02215
Currently, it is not understood how the specificity of the TCR guides CD4+ T cells into the conventional lineage (Tconv) vs directing them to become regulatory (Treg) cells defined by the Foxp3 transcription factor. To address this question, we made use of the "Limited" (LTD) mouse, which has a restricted TCR repertoire with a fixed TCR
chain and a TCR
chain minilocus. The TCR repertoires of Tconv and Treg cells were equally broad, were distinct, yet overlapped significantly, representing a less strict partition than previously seen between CD4 and CD8 T cells. As a group, the CDR3 motifs showed a significant trend to higher positive charge in Treg than in Tconv cells. The Tconv and Treg repertoires were both reshaped between thymus and periphery. Reducing the array of peptides presented by MHC class II molecules by introducing the H2-DMo/o mutation into the LTD mouse led to parallel shifts in the repertoires of Tconv and Treg cells. In both cases, the CDR3 elements were entirely different and strikingly shortened, relative to normal LTD mice. These peculiar sequences conferred reactivity to wild-type MHC class II complexes and were excluded from the normal repertoire, even among Treg cells, indicating that some forms of self-reactivity are incompatible with selection into the Treg lineage. In conclusion, the Treg repertoire is broad, with distinct composition and characteristics, yet significantly overlapping and sharing structural constraints with the repertoire of conventional CD4+ T cells.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant R01 AI51530 (to C.B. and D.M.), the William T. Young Chairs in Diabetes Research, and Joslin’s National Institute of Diabetes and Digestive and Kidney Diseases-funded Diabetes and Endocrinology Research Center cores. R.O. was supported by fellowships from the German Research Council (Deutsche Forschungsgemeinschaft, OB 150/2-1) and the Cancer Research Institute.
2 Current address: Institute for Immunology, Ludwig-Maximilians-Universität, Munich, Goethestrasse 31, D-80336 Munich, Germany.
3 Current address: Laboratory of Microbiology and Immunology of Infection, Institute for Molecular and Cell Biology, Rua do Campo Alegre, 823 4150-180, Porto, Portugal.
4 Current address: Division of Hematology/Oncology, Children’s Hospital, Boston, MA 02215.
5 Address correspondence and reprint requests to Drs. Diane Mathis and Christophe Benoist, Section on Immunology and Immunogenetics, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail address: cbdm{at}joslin.harvard.edu
6 Abbreviations used in this paper: WT, wild type; Treg, regulatory T; Tconv, conventional lineage T; LTD, Limited; LN, lymph node; ACE, abundance-based coverage estimator; MH, Morisita-Horn; SP, single positive; DP, double positive.
7 The online version of this article contains supplemental material.
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