Single-cell expression profiling of visceral adipose tissue and splenic CD4+ T cells from Treg-bmal1WT and Treg-bmal1KO mice at ZT0 and ZT12.
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ABSTRACT: Single-cell expression profiling of visceral adipose tissue and splenic CD4+ T cells from Treg-bmal1WT and Treg-bmal1KO mice at ZT0 and ZT12.
Project description:we reported single-cell gene expression of CD4+ T cells from the visceral adipose tissue of from male Foxp3-Cre.YFP bmal1WT or Foxp3-Cre.YFP bmal1flox/flox mice, and from spleen from bmal1WT mice, at ZT0 or ZT12. We found that VAT Tregs could be subdivided into five subtypes: p1 ST2+, p2 ST2+, Tbet+, IL18r+ and resting clusters. We found diurnal variation within the ST2+ subgroups, where the more activated p1 ST2+ Tregs were more represented at ZT0 in WT VAT Tregs. Such variations were not observed in splenic Tregs. In contrast, bmal1KO VAT Tregs were were enriched in the ST2+ Tregs, and had a constitutively high proportion of the p1 ST2+ subtype at ZT0 and ZT12.
Project description:Foxp3+CD4+ regulatory T cells (Tregs) regulate most types of immune response as well as several processes important for tissue homeostasis – for example, metabolism and repair. Dedicated Treg compartments – with distinct transcriptomes, T-cell-receptor repertoires, and growth/survival factor dependencies – have been identified in several nonlymphoid tissues. These Tregs are specifically adapted to function and operate in their home tissue – when, where and how do they take on their specialized characteristics? We recently reported that a splenic Treg population expressing low levels of the transcription factor, PPARg, contains precursors of Tregs residing in visceral adipose tissue. This finding made sense given that PPARg, the “master-regulator” of adipocyte differentiation, is required for the accumulation and function of Tregs in visceral adipose tissue but not in lymphoid tissues. Here we use single-cell RNA sequencing, single-cell Tcra and Tcrb sequencing, and adoptive-transfer experiments to show that, unexpectedly, the splenic PPARglo Treg population is transcriptionally heterogeneous and engenders Tregs in multiple nonlymphoid tissues beyond visceral adipose tissue, e.g. skin and liver. The existence of a general pool of splenic precursors for nonlymphoid-tissue Tregs opens new possibilities for regulating their emergence experimentally or therapeutically.
Project description:Foxp3+CD4+ regulatory T cells (Tregs) regulate most types of immune response as well as several processes important for tissue homeostasis – for example, metabolism and repair. Dedicated Treg compartments – with distinct transcriptomes, T-cell-receptor repertoires, and growth/survival factor dependencies – have been identified in several nonlymphoid tissues. These Tregs are specifically adapted to function and operate in their home tissue – when, where and how do they take on their specialized characteristics? We recently reported that a splenic Treg population expressing low levels of the transcription factor, PPARg, contains precursors of Tregs residing in visceral adipose tissue. This finding made sense given that PPARg, the “master-regulator” of adipocyte differentiation, is required for the accumulation and function of Tregs in visceral adipose tissue but not in lymphoid tissues. Here we use single-cell RNA sequencing, single-cell Tcra and Tcrb sequencing, and adoptive-transfer experiments to show that, unexpectedly, the splenic PPARglo Treg population is transcriptionally heterogeneous and engenders Tregs in multiple nonlymphoid tissues beyond visceral adipose tissue, e.g. skin and liver. The existence of a general pool of splenic precursors for nonlymphoid-tissue Tregs opens new possibilities for regulating their emergence experimentally or therapeutically.
Project description:Foxp3+CD4+ regulatory T cells (Tregs) regulate most types of immune response as well as several processes important for tissue homeostasis – for example, metabolism and repair. Dedicated Treg compartments – with distinct transcriptomes, T-cell-receptor repertoires, and growth/survival factor dependencies – have been identified in several nonlymphoid tissues. These Tregs are specifically adapted to function and operate in their home tissue – when, where and how do they take on their specialized characteristics? We recently reported that a splenic Treg population expressing low levels of the transcription factor, PPARg, contains precursors of Tregs residing in visceral adipose tissue. This finding made sense given that PPARg, the “master-regulator” of adipocyte differentiation, is required for the accumulation and function of Tregs in visceral adipose tissue but not in lymphoid tissues. Here we use single-cell RNA sequencing, single-cell Tcra and Tcrb sequencing, and adoptive-transfer experiments to show that, unexpectedly, the splenic PPARglo Treg population is transcriptionally heterogeneous and engenders Tregs in multiple nonlymphoid tissues beyond visceral adipose tissue, e.g. skin and liver. The existence of a general pool of splenic precursors for nonlymphoid-tissue Tregs opens new possibilities for regulating their emergence experimentally or therapeutically.
Project description:We reported transcriptional characterization of Treg and Tconv cells from thymic, splenic, and visceral adipose tissue (VAT) of vTreg53 TCR transgenic mice and control littermates. We examined the effect of Foxp3 on splenic and VAT CD4+ T cell transcriptome. We profiled gene expression in a novel PPARg+ splenic Treg population. We uncovered that the characteristic phenotype of VAT Treg cells was acquired in two stages.
Project description:Regulatory T (Treg) cells located within parenchymal tissues safeguard tissue homeostasis. A paradigmatic "tissue-Treg" population is that found in visceral-adipose tissue (VAT) of male mice. VAT-Treg cells have a unique transcriptome, are clonally expanded, and promote metabolic health through effects on local immunocytes and adipocytes. Because of their rarity and inaccessibility, cardinal questions such as what factors control their accumulation in fat and when/where/how do they adopt their distinctive phenotype remained unanswered. We addressed these issues using VAT- Treg T-cell-receptor (TCR) transgenic mice. Accumulation of VAT-Tregs was driven by combined effects of TCR specificity, Foxp3 expression, and a cell-intrinsic response to interleukin-33. Their characteristic phenotype emerged in two stages: a minority of splenic Treg cells weakly up-regulated a slice of the VAT-Treg transcriptional signature, reflecting cell activation, but the definitive phenotype, arming cells for fat survival, was manifest only in VAT. This deeper understanding of tissue-Treg generation should facilitate precision-targeting strategies.
Project description:We reported transcriptional characterization of vTreg53 TCR transgenic Treg cells from splenic and visceral adipose tissue (VAT) in mice fed with normal chow diet (NCD) or high fat diet (HFD) for different durations. We also reported transcriptional profile of VAT Treg cells stimulated by IFNa in vitro. Through this analysis, we found that the reduction of VAT Treg cells during obesity is driven by increased production of IFNa in VAT.