title: High TCR diversity ensures optimal function and homeostasis of Foxp3+ regulatory T cells.
abstract: 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.
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Föhse
authors.forename: Janine
authors.initials: J
authors.lastname: Suffner
authors.forename: Karsten
authors.initials: K
authors.lastname: Suhre
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wahl
authors.forename: Cornelia
authors.initials: C
authors.lastname: Lindner
authors.forename: Chun-Wei
authors.initials: CW
authors.lastname: Lee
authors.forename: Susanne
authors.initials: S
authors.lastname: Schmitz
authors.forename: Jan D
authors.initials: JD
authors.lastname: Haas
authors.forename: Stella
authors.initials: S
authors.lastname: Lamprecht
authors.forename: Christian
authors.initials: C
authors.lastname: Koenecke
authors.forename: André
authors.initials: A
authors.lastname: Bleich
authors.forename: Günter J
authors.initials: GJ
authors.lastname: Hämmerling
authors.forename: Bernard
authors.initials: B
authors.lastname: Malissen
authors.forename: Sebastian
authors.initials: S
authors.lastname: Suerbaum
authors.forename: Reinhold
authors.initials: R
authors.lastname: Förster
authors.forename: Immo
authors.initials: I
authors.lastname: Prinz
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002469:Cell Separation; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology*; D006086:Graft vs Host Disease / Q000276:immunology; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D017634:Self Tolerance / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D011948:Receptors, Antigen, T-Cell