Dataset Information

A Stat6/Pten axis links cold exposure with T cell tolerance in adipose tissue

ABSTRACT: Obesity and type-2 diabetes are associated with tissue-inflammation and metabolic defects in fat depots. Foxp3+regulatory T(Treg) cells mediate T-cell tolerance, thereby controlling tissue inflammation. However, the molecular underpinnings how environmental stimuli interlink T-cell tolerance with adipose tissue function remain largely unknown. Here, we report that cold exposure or beta3-adrenergic receptor (ADRB3) stimulation induces T-cell tolerance in vitro and in murine and humanized models. Tolerance induction was verified by CD4+T-cell-proteomes revealing higher protein expression of Foxp3 regulatory networks. Specifically, Ragulator-interacting protein C17orf59, which limits mTORC1 activity, was upregulated by either ADRB3-stimulation or cold-exposure, and therefore might enhance Treg induction. By loss and gain-of-function studies, including Treg depletion and transfers in vivo, we demonstrated that a T-cell-specific Stat6/Pten axis links cold-exposure or ADRB3 stimulation with Foxp3+Treg induction and adipose tissue function. Our findings open new avenues in understanding tissue-specific T-cell tolerance and the design of precision concepts toward personalized immune-metabolic health.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain, T Cell

SUBMITTER: Mario Oroshi

LAB HEAD: Carolin Daniel

PROVIDER: PXD004671 | Pride | 2017-09-11

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20151217_QEp2_LC12_1_FaHo_SA_StKr_CL_06.raw	Raw
	20151217_QEp2_LC12_1_FaHo_SA_StKr_NaCl_06.raw	Raw
	20151217_QEp2_LC12_1_FaHo_SA_StKr_library_01.raw	Raw
	20151217_QEp2_LC12_1_FaHo_SA_StKr_library_02.raw	Raw
	20151217_QEp2_LC12_1_FaHo_SA_StKr_library_03.raw	Raw

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Publications

A Stat6/Pten Axis Links Regulatory T Cells with Adipose Tissue Function.

Kälin Stefanie S Becker Maike M Ott Verena B VB Serr Isabelle I Hosp Fabian F Mollah Mohammad M H MMH Keipert Susanne S Lamp Daniel D Rohner-Jeanrenaud Francoise F Flynn Victoria K VK Scherm Martin G MG Nascimento Lucas F R LFR Gerlach Katharina K Popp Vanessa V Dietzen Sarah S Bopp Tobias T Krishnamurthy Purna P Kaplan Mark H MH Serrano Manuel M Woods Stephen C SC Tripal Philipp P Palmisano Ralf R Jastroch Martin M Blüher Matthias M Wolfrum Christian C Weigmann Benno B Ziegler Anette-Gabriele AG Mann Matthias M Tschöp Matthias H MH Daniel Carolin C

Cell metabolism 20170901 3

Obesity and type 2 diabetes are associated with metabolic defects and adipose tissue inflammation. Foxp3<sup>+</sup> regulatory T cells (Tregs) control tissue homeostasis by counteracting local inflammation. However, if and how T cells interlink environmental influences with adipocyte function remains unknown. Here, we report that enhancing sympathetic tone by cold exposure, beta3-adrenergic receptor (ADRB3) stimulation or a short-term high-calorie diet enhances Treg induction in vitro and in vi ...[more]

PMID: 28877454

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Project description:Regulatory T (Treg) cells are involved in self tolerance, immune homeostasis, prevention of autoimmunity, and suppression of immunity to pathogens or tumours. The forkhead transcription factor FOXP3 is essential for Treg cell development and function as mutations in FOXP3 cause severe autoimmunity in mice and humans. However, the FOXP3-dependent molecular mechanisms leading to this severe phenotype are not well understood. Here we introduce the chromatin remodelling enzyme SATB1 (special AT-rich sequence-binding protein-1) as an important target gene of FOXP3. So far, SATB1 has been associated with normal thymic T-cell development, peripheral T-cell homeostasis, TH1/TH2 polarization, and reprogramming of gene expression. In natural and induced murine and human FOXP3+ Treg cells SATB1 expression is significantly reduced. While there is no differential epigenetic regulation of the SATB1 locus between Treg and Teffector cells, FOXP3 reduces SATB1 expression directly as a transcriptional repressor at the SATB1 locus and indirectly via miR-155 induction, which specifically binds to the 3’UTR of the SATB1 mRNA. Reduced SATB1 expression in FOXP3+ cells achieved either by overexpression or induction of FOXP3 is linked to significant reduction in TH1 and TH2 cytokines, while loss of FOXP3 function either by knock down or genetic mutation leads to significant upregulation of SATB1 and subsequent cytokine production. Alltogether, these findings demonstrate that reduced SATB1 expression in Treg cells is necessary for maintenance of a Treg-cell phenotype in vitro and in vivo and places SATB1-mediated T cell-specific modulation of global chromatin remodelling central during the decision process between effector and regulatory T-cell function. Gene expression profiling of freshly isolated CD4+ T cells, separated into CD25 negative and positive subpopulations, from three different donors. FOXP3 is stably and constitutively expressed at a high level in CD4+CD25+ regulatory T cells and at a low level in CD4+CD25- cells.