High TCR diversity ensures optimal function andhomeostasis of Foxp3+ regulatory Tcells

• Published in: European journal of immunology 2011-11, Vol.41 (11), p.3101-3113
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Experimental GvHD; Foxp3; High‐throughput sequencing; Immune system; T cell receptors; TCR repertoire; Treg cells; Treg‐homeostasis
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201141986

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.