Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 41, Issue 11, Pages 3101-3113Publisher
WILEY
DOI: 10.1002/eji.201141986
Keywords
Experimental GvHD; Foxp3; High-throughput sequencing; TCR repertoire; Treg cells; Treg-homeostasis
Categories
Funding
- Deutsche Forschungsgemeinschaft [SFB621-A14]
- Deutsch-Franzosische Hochschule/Universite franco-allemande DFH-UFA [G2RFA 104-07-II]
- Hannover Biomedical Research School
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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.
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