High TCR diversity ensures optimal function and homeostasis of Foxp3+ regulatory T cells
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High TCR diversity ensures optimal function and homeostasis of Foxp3+ regulatory T cells. / Föhse, Lisa; Suffner, Janine; Suhre, Karsten; Wahl, Benjamin; Lindner, Cornelia; Lee, Chun-Wei; Schmitz, Susanne; Haas, Jan D; Lamprecht, Stella; Koenecke, Christian; Bleich, André; Hämmerling, Günter J; Malissen, Bernard; Suerbaum, Sebastian; Förster, Reinhold; Prinz, Immo.
In: EUR J IMMUNOL, Vol. 41, No. 11, 11.2011, p. 3101-13.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - High TCR diversity ensures optimal function and homeostasis of Foxp3+ regulatory T cells
AU - Föhse, Lisa
AU - Suffner, Janine
AU - Suhre, Karsten
AU - Wahl, Benjamin
AU - Lindner, Cornelia
AU - Lee, Chun-Wei
AU - Schmitz, Susanne
AU - Haas, Jan D
AU - Lamprecht, Stella
AU - Koenecke, Christian
AU - Bleich, André
AU - Hämmerling, Günter J
AU - Malissen, Bernard
AU - Suerbaum, Sebastian
AU - Förster, Reinhold
AU - Prinz, Immo
N1 - Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2011/11
Y1 - 2011/11
N2 - Dominant tolerance to self-antigen requires the presence of sufficient numbers of CD4(+) Foxp3(+) Treg cells with matching antigen specificity. However, the size and role of TCR repertoire diversity for antigen-specific immuno-regulation through Treg cells is not clear. Here, we developed and applied a novel high-throughput (HT) TCR sequencing approach to analyze the TCR repertoire of Treg cells and revealed the importance of high diversity for Treg-cell homeostasis and function. We found that highly polyclonal Treg cells from WT mice vigorously expanded after adoptive transfer into non-lymphopenic TCR-transgenic recipients with low Treg-cell diversity. In that system, we identified specific Treg-cell TCR preferences in distinct anatomic locations such as the mesenteric LN indicating that Treg cells continuously compete for MHC class-II-presented self-, food-, or flora-antigen. Functionally, we showed that high TCR diversity was required for optimal suppressive function of Treg cells in experimental acute graft versus host disease (GvHD). In conclusion, we suggest that efficient immuno-regulation by Treg cells requires high TCR diversity. Thereby, continuous competition of peripheral Treg cells for limited self-antigen shapes an organ-optimized, yet highly diverse, local TCR repertoire.
AB - Dominant tolerance to self-antigen requires the presence of sufficient numbers of CD4(+) Foxp3(+) Treg cells with matching antigen specificity. However, the size and role of TCR repertoire diversity for antigen-specific immuno-regulation through Treg cells is not clear. Here, we developed and applied a novel high-throughput (HT) TCR sequencing approach to analyze the TCR repertoire of Treg cells and revealed the importance of high diversity for Treg-cell homeostasis and function. We found that highly polyclonal Treg cells from WT mice vigorously expanded after adoptive transfer into non-lymphopenic TCR-transgenic recipients with low Treg-cell diversity. In that system, we identified specific Treg-cell TCR preferences in distinct anatomic locations such as the mesenteric LN indicating that Treg cells continuously compete for MHC class-II-presented self-, food-, or flora-antigen. Functionally, we showed that high TCR diversity was required for optimal suppressive function of Treg cells in experimental acute graft versus host disease (GvHD). In conclusion, we suggest that efficient immuno-regulation by Treg cells requires high TCR diversity. Thereby, continuous competition of peripheral Treg cells for limited self-antigen shapes an organ-optimized, yet highly diverse, local TCR repertoire.
KW - Adoptive Transfer
KW - Animals
KW - Cell Separation
KW - Flow Cytometry
KW - Forkhead Transcription Factors/genetics
KW - Graft vs Host Disease/immunology
KW - High-Throughput Nucleotide Sequencing/methods
KW - Homeostasis/genetics
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Transgenic
KW - Receptors, Antigen, T-Cell/genetics
KW - Self Tolerance/genetics
KW - T-Lymphocytes, Regulatory/immunology
U2 - 10.1002/eji.201141986
DO - 10.1002/eji.201141986
M3 - SCORING: Journal article
C2 - 21932448
VL - 41
SP - 3101
EP - 3113
JO - EUR J IMMUNOL
JF - EUR J IMMUNOL
SN - 0014-2980
IS - 11
ER -