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Brown adipose tissue harbors a distinct sub-population of regulatory T cells.

Medrikova D, Sijmonsma TP, Sowodniok K, Richards DM, Delacher M, Sticht C, Gretz N, Schafmeier T, Feuerer M, Herzig S - PLoS ONE (2015)

Bottom Line: Regulatory T (Treg) cells are critical determinants of both immune responses and metabolic control.Indeed, BAT harbored a unique sub-set of Treg cells characterized by a unique gene signature.As these Treg cells respond to BAT activation upon cold exposure, this study defines a BAT-specific Treg sub-set with direct implications for the regulation of energy homeostasis in response to environmental stress.

View Article: PubMed Central - PubMed

Affiliation: Joint Research Division Molecular Metabolic Control, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital, Heidelberg University, 69120, Heidelberg, Germany.

ABSTRACT
Regulatory T (Treg) cells are critical determinants of both immune responses and metabolic control. Here we show that systemic ablation of Treg cells compromised the adaptation of whole-body energy expenditure to cold exposure, correlating with impairment in thermogenic marker gene expression and massive invasion of pro-inflammatory macrophages in brown adipose tissue (BAT). Indeed, BAT harbored a unique sub-set of Treg cells characterized by a unique gene signature. As these Treg cells respond to BAT activation upon cold exposure, this study defines a BAT-specific Treg sub-set with direct implications for the regulation of energy homeostasis in response to environmental stress.

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Related in: MedlinePlus

Genotypical comparison of Treg and Tconv cells isolated from brown adipose tissue (BAT) and spleen tissue (SPL) in cold- and warm-conditioned animals generated with an Illumina Mouse Expression Array.(A) Gene expression profiles comparing Treg (top) or Tconv (bottom) cell populations between spleen and adipose tissue samples isolated from warm-conditioned animals (left) or between cells isolated from cold vs warm-conditioned animals (right). Numbers indicate genes either up- or downregulated more than 2-fold (cut-off: dotted line), with the number of significantly different (p<0.05) genes shown in brackets with an asterisk. (B) Volcano plot comparing gene expression and significance values between Treg and Tconv genes isolated from BAT in warm-conditioned animals. Key up- or downregulated genes in Treg cells are annotated (Foxp3, Il10, Cxcl1/2, Tcf7, Ifng) and serve as quality control to the published consensus Treg-cell signature. (C) Hierarchical clustering of the top-30 upregulated genes and the top-10 downregulated genes in warm-conditioned brown adipose tissue Treg cells versus spleen Treg cells. (D) Comparison of BAT-Treg-specific genes with visceral adipose tissue (VAT)-specific genes. We first determined 430 genes to upregulated in BAT warm-conditioned Treg cells, with 222 genes being significantly altered (p<0.05). We then overlaid BAT Treg-upregulated genes with VAT Treg tissue specific expression gene data. 181 genes were matched between both microarary chips, with 169 genes also upregulated in VAT, and only 12 genes specific for BAT (left). The corresponding analysis of the 516 genes upregulated in cold BAT Treg cells versus warm spleen Treg cells revealed 194 genes to be significantly upregulated. 158 could be matched to VAT Treg-specific genes, of which 148 were VAT-specific, whereas only 10 were specific for BAT. P-values indicate the significance of overrepresentation of BAT Treg-specific genes in the VAT Treg signature. (E) Comparison of VAT-Treg specific genes on BAT warm (left) or BAT cold (right) gene signatures. Of 1839 genes specifically overexpressed in VAT Treg cells, 1059 were statistically significantly (p<0.05) upregulated. Of these 1059 genes, 829 were also detectable in the BAT Treg microarray. When comparing the VAT Treg signature to warm BAT Treg cells, 660 genes were overrepresented in VAT, whereas cold BAT Treg cells show 685 genes to be overrepresented in VAT.
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pone.0118534.g001: Genotypical comparison of Treg and Tconv cells isolated from brown adipose tissue (BAT) and spleen tissue (SPL) in cold- and warm-conditioned animals generated with an Illumina Mouse Expression Array.(A) Gene expression profiles comparing Treg (top) or Tconv (bottom) cell populations between spleen and adipose tissue samples isolated from warm-conditioned animals (left) or between cells isolated from cold vs warm-conditioned animals (right). Numbers indicate genes either up- or downregulated more than 2-fold (cut-off: dotted line), with the number of significantly different (p<0.05) genes shown in brackets with an asterisk. (B) Volcano plot comparing gene expression and significance values between Treg and Tconv genes isolated from BAT in warm-conditioned animals. Key up- or downregulated genes in Treg cells are annotated (Foxp3, Il10, Cxcl1/2, Tcf7, Ifng) and serve as quality control to the published consensus Treg-cell signature. (C) Hierarchical clustering of the top-30 upregulated genes and the top-10 downregulated genes in warm-conditioned brown adipose tissue Treg cells versus spleen Treg cells. (D) Comparison of BAT-Treg-specific genes with visceral adipose tissue (VAT)-specific genes. We first determined 430 genes to upregulated in BAT warm-conditioned Treg cells, with 222 genes being significantly altered (p<0.05). We then overlaid BAT Treg-upregulated genes with VAT Treg tissue specific expression gene data. 181 genes were matched between both microarary chips, with 169 genes also upregulated in VAT, and only 12 genes specific for BAT (left). The corresponding analysis of the 516 genes upregulated in cold BAT Treg cells versus warm spleen Treg cells revealed 194 genes to be significantly upregulated. 158 could be matched to VAT Treg-specific genes, of which 148 were VAT-specific, whereas only 10 were specific for BAT. P-values indicate the significance of overrepresentation of BAT Treg-specific genes in the VAT Treg signature. (E) Comparison of VAT-Treg specific genes on BAT warm (left) or BAT cold (right) gene signatures. Of 1839 genes specifically overexpressed in VAT Treg cells, 1059 were statistically significantly (p<0.05) upregulated. Of these 1059 genes, 829 were also detectable in the BAT Treg microarray. When comparing the VAT Treg signature to warm BAT Treg cells, 660 genes were overrepresented in VAT, whereas cold BAT Treg cells show 685 genes to be overrepresented in VAT.

Mentions: The overall importance of Treg cells for WAT function prompted us to explore the molecular nature of BAT-associated Treg cells. To this end, wild-type C57Bl6 mice were either acclimatized to 30°C or challenged with a 12°C cold exposure for 2 days. After the corresponding acclimatization periods, BAT depots as well as the spleens were collected and Treg cells were sorted out of the corresponding tissue by fluorescence-associated cell sorting (FACS) followed by RNA purification and hybridization to an expression array. Microarray gene expression profiling revealed 430 genes to be more than twofold upregulated in BAT Treg cells compared to splenic Treg cells, with 222 genes significant between three replicates (Fig. 1A). Confirmation of lineage-specific genes in BAT Treg versus BAT Tconv T cells included classic Treg genes such as Foxp3 and cytotoxic T-lymphocyte-associated protein 4 (Ctla4) as over-represented and special AT-rich sequence binding protein 1 (Satb1) and transcription factor 7, T cell specific (Tcf7) as under-represented genes. In addition, chemokine (C-X-C motif) ligand (Cxcl) 1 and 2, and interleukin (IL) 10 were highly over-expressed in BAT Treg cells (Fig. 1B). The top 30 significantly upregulated genes and bottom 10 downregulated genes in BAT Treg cells were then subjected to unsupervised hierarchical clustering (Fig. 1C), which revealed a unique gene expression signature for BAT Treg cells compared to splenic regulatory and conventional T (Tconv) cells as well as BAT Tconv cells. We then compared the BAT Treg gene signature to the VAT-specific gene signature [7], which stratified most of the genes identified in both microarrays to be specific for a general fat Treg gene signature (Fig. 1D, E). However, a specific BAT Treg gene signature could also be discerned, which was independent of the WAT Treg signature (Table 1).


Brown adipose tissue harbors a distinct sub-population of regulatory T cells.

Medrikova D, Sijmonsma TP, Sowodniok K, Richards DM, Delacher M, Sticht C, Gretz N, Schafmeier T, Feuerer M, Herzig S - PLoS ONE (2015)

Genotypical comparison of Treg and Tconv cells isolated from brown adipose tissue (BAT) and spleen tissue (SPL) in cold- and warm-conditioned animals generated with an Illumina Mouse Expression Array.(A) Gene expression profiles comparing Treg (top) or Tconv (bottom) cell populations between spleen and adipose tissue samples isolated from warm-conditioned animals (left) or between cells isolated from cold vs warm-conditioned animals (right). Numbers indicate genes either up- or downregulated more than 2-fold (cut-off: dotted line), with the number of significantly different (p<0.05) genes shown in brackets with an asterisk. (B) Volcano plot comparing gene expression and significance values between Treg and Tconv genes isolated from BAT in warm-conditioned animals. Key up- or downregulated genes in Treg cells are annotated (Foxp3, Il10, Cxcl1/2, Tcf7, Ifng) and serve as quality control to the published consensus Treg-cell signature. (C) Hierarchical clustering of the top-30 upregulated genes and the top-10 downregulated genes in warm-conditioned brown adipose tissue Treg cells versus spleen Treg cells. (D) Comparison of BAT-Treg-specific genes with visceral adipose tissue (VAT)-specific genes. We first determined 430 genes to upregulated in BAT warm-conditioned Treg cells, with 222 genes being significantly altered (p<0.05). We then overlaid BAT Treg-upregulated genes with VAT Treg tissue specific expression gene data. 181 genes were matched between both microarary chips, with 169 genes also upregulated in VAT, and only 12 genes specific for BAT (left). The corresponding analysis of the 516 genes upregulated in cold BAT Treg cells versus warm spleen Treg cells revealed 194 genes to be significantly upregulated. 158 could be matched to VAT Treg-specific genes, of which 148 were VAT-specific, whereas only 10 were specific for BAT. P-values indicate the significance of overrepresentation of BAT Treg-specific genes in the VAT Treg signature. (E) Comparison of VAT-Treg specific genes on BAT warm (left) or BAT cold (right) gene signatures. Of 1839 genes specifically overexpressed in VAT Treg cells, 1059 were statistically significantly (p<0.05) upregulated. Of these 1059 genes, 829 were also detectable in the BAT Treg microarray. When comparing the VAT Treg signature to warm BAT Treg cells, 660 genes were overrepresented in VAT, whereas cold BAT Treg cells show 685 genes to be overrepresented in VAT.
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Related In: Results  -  Collection

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pone.0118534.g001: Genotypical comparison of Treg and Tconv cells isolated from brown adipose tissue (BAT) and spleen tissue (SPL) in cold- and warm-conditioned animals generated with an Illumina Mouse Expression Array.(A) Gene expression profiles comparing Treg (top) or Tconv (bottom) cell populations between spleen and adipose tissue samples isolated from warm-conditioned animals (left) or between cells isolated from cold vs warm-conditioned animals (right). Numbers indicate genes either up- or downregulated more than 2-fold (cut-off: dotted line), with the number of significantly different (p<0.05) genes shown in brackets with an asterisk. (B) Volcano plot comparing gene expression and significance values between Treg and Tconv genes isolated from BAT in warm-conditioned animals. Key up- or downregulated genes in Treg cells are annotated (Foxp3, Il10, Cxcl1/2, Tcf7, Ifng) and serve as quality control to the published consensus Treg-cell signature. (C) Hierarchical clustering of the top-30 upregulated genes and the top-10 downregulated genes in warm-conditioned brown adipose tissue Treg cells versus spleen Treg cells. (D) Comparison of BAT-Treg-specific genes with visceral adipose tissue (VAT)-specific genes. We first determined 430 genes to upregulated in BAT warm-conditioned Treg cells, with 222 genes being significantly altered (p<0.05). We then overlaid BAT Treg-upregulated genes with VAT Treg tissue specific expression gene data. 181 genes were matched between both microarary chips, with 169 genes also upregulated in VAT, and only 12 genes specific for BAT (left). The corresponding analysis of the 516 genes upregulated in cold BAT Treg cells versus warm spleen Treg cells revealed 194 genes to be significantly upregulated. 158 could be matched to VAT Treg-specific genes, of which 148 were VAT-specific, whereas only 10 were specific for BAT. P-values indicate the significance of overrepresentation of BAT Treg-specific genes in the VAT Treg signature. (E) Comparison of VAT-Treg specific genes on BAT warm (left) or BAT cold (right) gene signatures. Of 1839 genes specifically overexpressed in VAT Treg cells, 1059 were statistically significantly (p<0.05) upregulated. Of these 1059 genes, 829 were also detectable in the BAT Treg microarray. When comparing the VAT Treg signature to warm BAT Treg cells, 660 genes were overrepresented in VAT, whereas cold BAT Treg cells show 685 genes to be overrepresented in VAT.
Mentions: The overall importance of Treg cells for WAT function prompted us to explore the molecular nature of BAT-associated Treg cells. To this end, wild-type C57Bl6 mice were either acclimatized to 30°C or challenged with a 12°C cold exposure for 2 days. After the corresponding acclimatization periods, BAT depots as well as the spleens were collected and Treg cells were sorted out of the corresponding tissue by fluorescence-associated cell sorting (FACS) followed by RNA purification and hybridization to an expression array. Microarray gene expression profiling revealed 430 genes to be more than twofold upregulated in BAT Treg cells compared to splenic Treg cells, with 222 genes significant between three replicates (Fig. 1A). Confirmation of lineage-specific genes in BAT Treg versus BAT Tconv T cells included classic Treg genes such as Foxp3 and cytotoxic T-lymphocyte-associated protein 4 (Ctla4) as over-represented and special AT-rich sequence binding protein 1 (Satb1) and transcription factor 7, T cell specific (Tcf7) as under-represented genes. In addition, chemokine (C-X-C motif) ligand (Cxcl) 1 and 2, and interleukin (IL) 10 were highly over-expressed in BAT Treg cells (Fig. 1B). The top 30 significantly upregulated genes and bottom 10 downregulated genes in BAT Treg cells were then subjected to unsupervised hierarchical clustering (Fig. 1C), which revealed a unique gene expression signature for BAT Treg cells compared to splenic regulatory and conventional T (Tconv) cells as well as BAT Tconv cells. We then compared the BAT Treg gene signature to the VAT-specific gene signature [7], which stratified most of the genes identified in both microarrays to be specific for a general fat Treg gene signature (Fig. 1D, E). However, a specific BAT Treg gene signature could also be discerned, which was independent of the WAT Treg signature (Table 1).

Bottom Line: Regulatory T (Treg) cells are critical determinants of both immune responses and metabolic control.Indeed, BAT harbored a unique sub-set of Treg cells characterized by a unique gene signature.As these Treg cells respond to BAT activation upon cold exposure, this study defines a BAT-specific Treg sub-set with direct implications for the regulation of energy homeostasis in response to environmental stress.

View Article: PubMed Central - PubMed

Affiliation: Joint Research Division Molecular Metabolic Control, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital, Heidelberg University, 69120, Heidelberg, Germany.

ABSTRACT
Regulatory T (Treg) cells are critical determinants of both immune responses and metabolic control. Here we show that systemic ablation of Treg cells compromised the adaptation of whole-body energy expenditure to cold exposure, correlating with impairment in thermogenic marker gene expression and massive invasion of pro-inflammatory macrophages in brown adipose tissue (BAT). Indeed, BAT harbored a unique sub-set of Treg cells characterized by a unique gene signature. As these Treg cells respond to BAT activation upon cold exposure, this study defines a BAT-specific Treg sub-set with direct implications for the regulation of energy homeostasis in response to environmental stress.

Show MeSH
Related in: MedlinePlus