Stability of the Regulatory T Cell Lineage in Vivo

Rubtsov, Yuri P.; Niec, Rachel; Josefowicz, Steven Z.; Li, Li; Darce, Jaime; Mathis, Diane; Benoist, Christophe; Rudensky, Alexander Y.

doi:10.1126/science.1191996

Cited by 637 publications

(652 citation statements)

References 28 publications

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“…This result is strikingly similar to our observations in patients with RRMS treated with DAC HYP, wherein both rTregs and aTregs decline, FOXP3 expression is only modestly decreased (,10%), TSDR demethylation is maintained, and there is no increase in IL-2, IFNg, or IL-17 production. In addition, the result that Tregs in DAC HYP-treated patients maintained Ki-67 expression is of significance, because Treg self-renewal has been shown to be a major mechanism that maintains the Treg population (45). One possible caveat to our analysis would be if some Tregs completely lost expression of FOXP3 during CD25 blockade.…”

Section: Discussionmentioning

confidence: 61%

“…In mice, the majority of Tregs are stable during immune homeostasis; however, in certain inflammatory conditions Treg instability is observed (9,11,(44)(45)(46). The role of the IL-2 axis in this process is still unclear.…”

Section: Discussionmentioning

confidence: 99%

“…NOD mice, which have a genetic deficiency in IL-2 signaling, have decreased FOXP3 expression and increased propensity for Treg instability (9). Rubtsov et al (45) demonstrated that IL-2 deprivation led to a decrease in total FOXP3 + cells and a modest decrease in FOXP3 protein expression at the single-cell level, but it did not cause conversion of Tregs to an effector T cell phenotype (45). This result is strikingly similar to our observations in patients with RRMS treated with DAC HYP, wherein both rTregs and aTregs decline, FOXP3 expression is only modestly decreased (,10%), TSDR demethylation is maintained, and there is no increase in IL-2, IFNg, or IL-17 production.…”

Section: Discussionmentioning

confidence: 99%

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In Vivo Maintenance of Human Regulatory T Cells during CD25 Blockade

Huss

Mehta

Sharma

et al. 2015

The Journal of Immunology

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Regulatory T cells (Tregs) mediate immune tolerance to self and depend on IL-2 for homeostasis. Treg deficiency, dysfunction, and instability are implicated in the pathogenesis of numerous autoimmune diseases. There is considerable interest in therapeutic modulation of the IL-2 pathway to treat autoimmunity, facilitate transplantation tolerance, or potentiate tumor immunotherapy. Daclizumab is a humanized mAb that binds the IL-2 receptor α subunit (IL-2Rα or CD25) and prevents IL-2 binding. In this study, we investigated the effect of daclizumab-mediated CD25 blockade on Treg homeostasis in patients with relapsing-remitting multiple sclerosis. We report that daclizumab therapy caused an ∼50% decrease in Tregs over a 52-wk period. Remaining FOXP3+ cells retained a demethylated Treg-specific demethylated region in the FOXP3 promoter, maintained active cell cycling, and had minimal production of IL-2, IFN-γ, and IL-17. In the presence of daclizumab, IL-2 serum concentrations increased and IL-2Rβγ signaling induced STAT5 phosphorylation and sustained FOXP3 expression. Treg declines were not associated with daclizumab-related clinical benefit or cutaneous adverse events. These results demonstrate that Treg phenotype and lineage stability can be maintained in the face of CD25 blockade.

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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In Vivo Maintenance of Human Regulatory T Cells during CD25 Blockade

Huss

Mehta

Sharma

et al. 2015

The Journal of Immunology

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“…The recruitment of effector cells to sites of infection is driven by local tissue cues as well as pathogen signals, and the pro‐inflammatory milieu at these sites may contribute to the shaping of the phenotype of the cells once they arrive 19, 71. It is now emerging that in addition to these classic cytokine/cytokine receptor‐mediated signals, T cells are also highly responsive to other metabolic cues, and these are also sensed by surface receptors and biochemical pathways.…”

Section: Tissue and Metabolic Cues Can Alter Transcriptional Programmmentioning

confidence: 99%

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

et al. 2018

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Regulatory T cells (Treg) are critical for preventing autoimmunity and curtailing responses of conventional effector T cells (Tconv). The reprogramming of T‐cell fate and function to generate Treg requires switching on and off of key gene regulatory networks, which may be initiated by a subtle shift in expression levels of specific genes. This can be achieved by intermediary regulatory processes that include microRNA and long noncoding RNA‐based regulation of gene expression. There are well‐documented microRNA profiles in Treg and Tconv, and these can operate to either reinforce or reduce expression of a specific set of target genes, including FOXP3 itself. This type of feedforward/feedback regulatory loop is normally stable in the steady state, but can alter in response to local cues or genetic risk. This may go some way to explaining T‐cell plasticity. In addition, in chronic inflammation or autoimmunity, altered Treg/Tconv function may be influenced by changes in enhancer–promoter interactions, which are highly cell type‐specific. These interactions are impacted by genetic risk based on genome‐wide association studies and may cause subtle alterations to the gene regulatory networks controlled by or controlling FOXP3 and its target genes. Recent insights into the 3D organisation of chromatin and the mapping of noncoding regulatory regions to the genes they control are shedding new light on the direct impact of genetic risk on T‐cell function and susceptibility to inflammatory and autoimmune conditions.

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“…Therefore, the stable expression of Foxp3 is critical, and it is still contentious whether Foxp3 instability is pathologically relevant (17)(18)(19)(20)(21). Stable expression of Foxp3 is accompanied by epigenetic modulation of the CpG-rich conserved noncoding sequence 2 (CNS2) within the first intron of the Foxp3 locus (22)(23)(24)(25).…”

Section: Vitamin C Facilitates Demethylation Of the Foxp3 Enhancer Inmentioning

confidence: 99%

Vitamin C Facilitates Demethylation of the Foxp3 Enhancer in a Tet-Dependent Manner

Nair

Song

2016

The Journal of Immunology

147

100

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Demethylation of CpG motifs in the Foxp3 intronic element, conserved noncoding sequence 2 (CNS2), is indispensable for the stable expression of Foxp3 in regulatory T cells (Tregs). In this study, we found that vitamin C induces CNS2 demethylation in Tregs in a ten-eleven-translocation 2 (Tet2)-dependent manner. The CpG motifs of CNS2 in Tregs generated in vitro by TGF-β (iTregs), which were methylated originally, became demethylated after vitamin C treatment. The conversion of 5-methylcytosin into 5-hydroxymethylcytosin was more efficient, and the methyl group from the CpG motifs of Foxp3 CNS2 was erased rapidly in iTregs treated with vitamin C. The effect of vitamin C disappeared in Tet2−/− iTregs. Furthermore, CNS2 in peripheral Tregs in vivo, which were demethylated originally, became methylated after treatment with a sodium-dependent vitamin C transporter inhibitor, sulfinpyrazone. Finally, CNS2 demethylation in thymic Tregs was also impaired in Tet2−/− mice, but not in wild type mice, when they were treated with sulfinpyrazone. Collectively, vitamin C was required for the CNS2 demethylation mediated by Tet proteins, which was essential for Foxp3 expression. Our findings indicate that environmental factors, such as nutrients, could bring about changes in immune homeostasis through epigenetic mechanisms.

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Stability of the Regulatory T Cell Lineage in Vivo

Cited by 637 publications

References 28 publications

In Vivo Maintenance of Human Regulatory T Cells during CD25 Blockade

In Vivo Maintenance of Human Regulatory T Cells during CD25 Blockade

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

Vitamin C Facilitates Demethylation of the Foxp3 Enhancer in a Tet-Dependent Manner

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