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Foxp3+ regulatory T cells control hypothalamic inflammation

ABSTRACT: The central nervous system (CNS) hypothalamus controls systemic metabolism. Inflammatory CNS processes evolving upon exposure to calorie-rich diet are thought to promote impaired metabolic CNS control, thereby triggering obesity and Type-2 diabetes (T2D). However, immune cells relevant for maintaining hypothalamic integrity remain incompletely understood. Here, we identify hypothalamic CD4+Foxp3+regulatory T(Treg) cells which control local tissue-inflammation. Specifically, upon exposure to a calorie-rich diet, a significant decline in hypothalamus-residing Foxp3+Tregs occurred and was accompanied by increased immune activation of CD4+T cells, infiltrating macrophages and microglia. Microglial proteomes of mice exposed to the hypercaloric challenge confirmed characteristics of immune activation; specifically, mRNA expression profiling of hypothalamic CD4+T cells indicated a Th1-mediated inflammatory state evidenced by high levels of Tbx21, Cxcr3, Cd226 and reduced expression of Ccr7 and S1P1 receptors relevant for recruitment to and retention at inflammatory sites. Using Treg depletion and transfer experiments in vivo, we found that Foxp3+Tregs critically limit hypothalamic immune activation induced by hyper-caloric challenge. Our findings open new avenues in the design of tailored concepts to improve immunometabolic health in obesity and T2D.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain, T Cell

SUBMITTER: Mario Oroshi

LAB HEAD: Carolin Daniel

PROVIDER: PXD004498 | Pride | 2025-01-20

REPOSITORIES: pride

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			Action	DRS
	20150620_EXQ00_FaHo_SA_StKr_control_01.raw	Raw
	20150620_EXQ00_FaHo_SA_StKr_control_02.raw	Raw
	20150620_EXQ00_FaHo_SA_StKr_control_03.raw	Raw
	20150620_EXQ00_FaHo_SA_StKr_highfat_01.raw	Raw
	20150620_EXQ00_FaHo_SA_StKr_highfat_02.raw	Raw

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Project description:The hypothalamus in the central nervous system (CNS) plays a key role in the control of systemic metabolism. A calorie-rich diet triggers CNS immune activation, which contributes to impairments of metabolic control, favoring obesity and Type 2 Diabetes (T2D). However, cell types and molecular processes regulating hypothalamic immune activation remain incompletely understood. Here, we report the functionally relevant presence of regulatory T cells (Tregs), key players in the control of immune and tissue homeostasis, in the hypothalamus. Exposure to calorie-rich environments triggers immune activation of hypothalamic CD4+T cells, infiltrating macrophages and microglia while decreasing the presence of hypothalamic Tregs in mice. mRNA expression profiling of hypothalamic CD4+T cells revealed a Th1-like activation state evidenced by high levels of Tbx21, Cxcr3 and Cd226 and a decrease of Ccr7 and S1pr1 expression, a profile typical for recruitment of T cells to and retention at inflammatory sites. Importantly, mechanistic Treg loss- and gain-of-function experiments in vivo, show that Foxp3+Tregs limit hypothalamic immune activation and improve metabolic impairments induced by hyper-caloric feeding. Our findings refine the current model of immuno-metabolic crosstalk in the brain in response to environmental challenges and are of relevance for the future development of immune interventions to support health in obesity and T2D.

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Regulatory T cells from colonic lamina propria [array]

Project description:The colonic lamina propria contains a distinct population of Foxp3+ T regulatory cells (Tregs) that modulate responses to commensal microbes. Analysis of gene expression revealed that the transcriptome of colonic Tregs is distinct from splenic and other tissue Tregs. Rorγ and Helios in colonic Tregs mark distinct populations: Rorγ+Helios- or Rorγ-Helios+ Tregs. We uncovered an unanticipated role for Rorγ, a transcription factor generally considered to be antagonistic to Foxp3. Rorγ in colonic Tregs accounts for a small but specific part of the colon-specific Treg signature. (1) Total colonic and splenic Foxp3+ Treg comparison: Lymphocytes were isolated from colonic lamina propria and spleens of Foxp3-ires-GFP mice, where GFP reports Foxp3 expression. TCRb+CD4+GFP+ cells were double sorted into Trizol. (2) Colonic Rorγ+ and Rorγ- Treg comparison: Foxp3-ires-Thy1.1 reporter mice were crossed to Rorc-GFP reporter mice to generate mice that report both Foxp3 and Rorγ expression. Rorγ+Foxp3+ Tregs (TCRb+CD4+Thy1.1+GFP+) and Rorγ-Foxp3+ Tregs (TCRb+CD4+Thy1.1+GFP-) from colonic lamina propria were double sorted into Trizol.To reduce variability and increase cell number, cells from multiple mice were pooled for sorting and at least three replicates were generated for all groups. RNA from 1.5-3.0 x104 cells was amplified, labeled and hybridized to Affymetrix Mouse Gene 1.0 ST Arrays.

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