Paper Reading
01
A Mutation inthe Transcription Factor Foxp3 Drives T Helper 2 Effector Function in Regulatory T Cells.
Van Gool F, Nguyen MLT, Mumbach MR,Satpathy AT, Rosenthal WL et alImmunity
Regulatory T (Treg) cells maintain immune tolerance through the master transcription factor forkhead box P3 (FOXP3), which is crucial for Treg cellfunction and homeostasis. IPEX (immune dysregulation polyendocrinopathy enteropathy X-linked) syndrome is a recessive disease affecting exclusively males.This life-threatening disease is characterized by widespread multi-organ autoimmunity,In 2001, genome linkage analysis and positional cloning identified theforkhead or winged helix family transcription factor forkhead box P3 (FOXP3) asthe gene responsible for the IPEX phenotype in humans (Bennett et al., 2001;Wildin et al., 2001) and scurfy phenotype in mice.To date, there are over 75 different FOXP3 mutations described in IPEXpatients (Bacchetta et al., ), which cluster in the N-terminal proline-richdomain, the central leucine zipper domain, and the C-terminal forkhead (FKH)domain.In this report, we identified a FOXP3gene mutation in a young male patient that manifested with severe IPEX syndromeand exhibited several signs of Th2-like disease.This mutation resulted in the substitution of methionine for isoleucine atamino acid 370 (M370I) located at the core of the dimerization motif in the FKHdomain of FOXP3. We hypothesized that this mutation in the domain-swap interface altered FOXP3 function and its transcriptional control of the Tregcell program, potentially causing transdifferentiation into Th2 cells. In order to perform a detailed phenotypic, biochemical, and functional analysis of this FOXP3 gene mutation, we generated a transgenic mouse that carrying a bacterial artificial chromosome (BAC) containing the mutant Foxp3 allele and recapitulatedthe the phenotype of the IPEX Patient. Introduction of the Foxp3 M370I genemutation led to the formation of impaired CD4+ Foxp3+ Treg cells with a highly plastic phenotype and the acquisition of a Th2-like program, resulting in the development of a Th2-biased autoimmune disease. Genomic analysis of Treg cells by RNA-sequencing, Foxp3 chromatin immuno precipitation followed by high-throughput DNA sequencing (ChIP-sequencing), and H3K27acHiChIP revealed aspecific de-repression of the Th2 transcriptional program leading to the generation of Th2-like Treg cells that were unable to suppress extrinsic Th2 cells. and revealed chromatin remodeling at the Th2 locus with an increase in enhancer-promoter interactions, de novo binding of M370I Foxp3 to the Th2 cytokine locus, and dysregulation of the locus leading to GATA3 and Th2 cytokines production by the Tregs and the resulting pathogenicity.
https://www.10.1016/j.immuni..12.016
02
Metabolic control ofTH17 and induced Treg cell
balance by an epigenetic mechanism
Tao Xu, Kelly M.Stewart, XiaohuWang et al
nature(Aug)
Metabolism has been shown to integrate with epigenetics and transcription to modulate cellfate and function. Here, through the discovery and mechanistic characterization of a small molecule,(aminooxy)acetic acid, that reprograms the differentiation of T helper 17(TH17) cells towards induced regulatory T (iTreg) cells, we show that increased transamination, mainly catalysed by GOT1, leads to increased levels of 2-hydroxyglutarate in differentiating TH17 cells. To identify small molecules that reprogram TH17 differentiation towards iTreg cellfate, we screened 10,000 small molecules using CD4+ naive T cells from IL-17F–RFP/FOXP3–GFP mice cultured under optimal TH17 differentiation conditions. A small molecule, (aminooxy)acetic acid(AOA), was found to reprogram TH17 induction to iTreg cells in a dose-dependent manner. we show that increased transamination, mainly catalysed by GOT1, leads to increased levels of 2- hydroxyl- glutaratein differentiating TH17 cells. The accumulation of 2-hydroxy-glutarate resulted in hypermethylation of the Foxp3 gene locus and inhibited Foxp3 transcription, which is essential for fate determination towards TH17 cells. Inhibition of the conversion of glutamate toα-ketoglutaric acid prevented the production of 2-hydroxyglutarate, reducedmethylation of the Foxp3 gene locus, and increased Foxp3 expression.This consequently blocked the differentiation ofTH17 cells by antagonizing the function of transcription factor RORγt andpromoted polarization into iTreg cells. Selective inhibition of GOT1 with(aminooxy)acetic acid ameliorated experimental autoimmune encephalomyelitis ina therapeutic mouse model by regulating the balance between TH17 and iTregcells. Targeting a glutamate-dependent metabolic pathway thus represents a new strategy for developing therapeutic agents against TH17-mediated autoimmune diseases.
/immunity/fulltext/S1074-7613(17)30125-5
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