Publication details

A mechanism for expansion of regulatory T-cell repertoire and its role in self-tolerance.

Authors	FENG Yongqiang VAN DER VEEKEN Joris SHUGAY Mikhail PUTINTSEVA Ekaterina V. OSMANBEYOGLU Hatice U. DIKIY Stanislav HOYOS Beatrice E. MOLTEDO Bruno HEMMERS Saskia TREUTING Piper LESLIE Christina S. CHUDAKOV Dmitriy RUDENSKY Alexander Y.
Year of publication	2015
Type	Article in Periodical
Magazine / Source	Nature
MU Faculty or unit	Central European Institute of Technology
Citation
Web	http://www.nature.com/doifinder/10.1038/nature16141
Doi	http://dx.doi.org/10.1038/nature16141
Field	Oncology and hematology
Keywords	T cell receptors; self-tolerance; expansion of regulatory
Description	T-cell receptor (TCR) signalling has a key role in determining T-cell fate. Precursor cells expressing TCRs within a certain low-affinity range for complexes of self-peptide and major histocompatibility complex (MHC) undergo positive selection and differentiate into naive T cells expressing a highly diverse self-MHC-restricted TCR repertoire. In contrast, precursors displaying TCRs with a high affinity for 'self' are either eliminated through TCR-agonist-induced apoptosis (negative selection) or restrained by regulatory T (Treg) cells, whose differentiation and function are controlled by the X-chromosome-encoded transcription factor Foxp3 (reviewed in ref. 2). Foxp3 is expressed in a fraction of self-reactive T cells that escape negative selection in response to agonist-driven TCR signals combined with interleukin 2 (IL-2) receptor signalling. In addition to Treg cells, TCR-agonist-driven selection results in the generation of several other specialized T-cell lineages such as natural killer T cells and innate mucosal-associated invariant T cells. Although the latter exhibit a restricted TCR repertoire, Treg cells display a highly diverse collection of TCRs. Here we explore in mice whether a specialized mechanism enables agonist-driven selection of Treg cells with a diverse TCR repertoire, and the importance this holds for self-tolerance. We show that the intronic Foxp3 enhancer conserved noncoding sequence 3 (CNS3) acts as an epigenetic switch that confers a poised state to the Foxp3 promoter in precursor cells to make Treg cell lineage commitment responsive to a broad range of TCR stimuli, particularly to suboptimal ones. CNS3-dependent expansion of the TCR repertoire enables Treg cells to control self-reactive T cells effectively, especially when thymic negative selection is genetically impaired. Our findings highlight the complementary roles of these two main mechanisms of self-tolerance.