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

Abstract

SUMMARYT cell receptor (TCR) signaling plays a key role in T cell fate determination. Precursor cells expressing TCRs within a certain low affinity range for self peptide-MHC complexes undergo positive selection and differentiate into naïve 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)1 or restrained by regulatory CD4+ T (Treg) cells, whose differentiation and function are controlled by the X-chromosome encoded transcription factor Foxp3 (review2). 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 signaling. In addition to Treg cells, TCR agonist-driven selection results in the generation of several other specialized T cell lineages like NKT and MAIT cells3. Although the latter exhibit a restricted TCR repertoire, Treg cells display a highly diverse collection of TCRs4-6, Here we explored whether a specialized mechanism enables agonist driven selection of Treg cells with a diverse TCR repertoire and its significance for self-tolerance. We found that intronic Foxp3 enhancer 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 effectively control self-reactive T cells, especially when thymic negative selection was genetically impaired. Our findings highlight the complementary roles of these two main mechanisms of self-tolerance.

Flicr , a long noncoding RNA, modulates Foxp3 expression and autoimmunity

“…However, Flicr does not seem to influence DNA methylation or chromatin accessibility at CNS2, but instead affects chromatin structure in the CNS3/AR5 region. CNS3 previously has been described as a poised enhancer open more generally in the T-cell lineage and important for Treg differentiation (41). Our results suggest this region also has a role in mature Tregs, balanced with AR5.…”

“…1D). Tissue Tregs tend to have activated phenotypes and, accordingly, Treg activation slightly reduced Flicr expression in vivo (41) and in vitro (42) (Fig. 1E).…”

Dynamics of Individual T Cell Repertoires: From Cord Blood to Centenarians

“…Multiple studies have been performed in recent years to characterize TCR repertoires either in general (13)(14)(15)(16)(17)(18)(19)(20)(21)(22) or at the level of functional T cell subsets (17,18,(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). However, these new opportunities have also brought new hidden pitfalls, which have not always been predicted, recognized, and proportionally addressed in the works published to date.…”

Epigenetic editing: How cutting-edge targeted epigenetic modification might provide novel avenues for autoimmune disease therapy

“…Demethylation of this region is found in T-reg cell precursors, even before Foxp3 is expressed, highlighting its importance in epigenetic “poising”. Interestingly, it does not appear to be involved in maintenance of FOXP3 expression following induction [87, 88]. The promoter region of FOXP3 also contains DNA methylation sites which are important in induction and long-term expression of the gene.…”