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Series GSE189476 Query DataSets for GSE189476
Status Public on Mar 29, 2022
Title Correcting altered immunological responses in obesity restores efficacy of targeted biologic therapy for inflammatory disease
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Decades of work have elucidated cytokine signaling and transcriptional pathways that control T cell differentiation and have led the way to targeted biologic therapies that are effective in a range of autoimmune, allergic, and inflammatory diseases. More recent evidence indicates that obesity and other shifts in systemic metabolism can also influence the function of cells in the immune system, although the mechanisms and possible effects on immunotherapy outcomes remain largely unknown. Here, using two models of atopic dermatitis (AD), we show that lean and obese mice mount strikingly different immune responses. Obesity converts the classical AD-associated type 2 T helper cell (TH2)-predominant disease into a more severe disease with prominent TH17 inflammation. In addition to this immunopathologic difference, we observed strikingly divergent responses to biologic therapies targeting TH2 cytokines, which robustly protected lean mice but significantly exacerbated disease in obese mice. Single-cell RNA sequencing (scRNA-seq) coupled with genome-wide binding analysis revealed decreased activity in nuclear receptor PPARg (peroxisome proliferator-activated receptor gamma) activity in TH2 cells from obese mice relative to lean mice. Conditional ablation of PPARg in T cells identified a novel function for PPARg as required for focusing the in vivo TH response towards a TH2-predominant state and preventing aberrant non-TH2 inflammation. Treatment of obese mice with a small molecule PPARg agonist prevented development of TH17 pathology in AD and unlocked robust therapeutic responsiveness to targeted anti-TH2 biologics. These studies reveal the effects of obesity on immunological disease and demonstrate a precision medicine approach to target the immune dysregulation caused by obesity to restore efficacy of a biological immunotherapy.
 
Overall design Mice were challenged with MC903-AD on their ears, and lesional CD4+ T cells were isolated by FACS sorting on Day 10 of the challenge for single cell sequencing using the 10X platform.
 
Contributor(s) Bapat SP, Mowery CT, Evans RM, Zheng Y, Marson A
Citation(s) 35355021
NIH grant(s)
Grant ID Grant title Affiliation Name
F30 DK096828 The Role of PPAR Gamma in Fat-Resident Regulatory T Cells and Glucose Homeostasis THE SALK INSTITUTE FOR BIOLOGICAL STUDIES Sagar Pradeep Bapat
K38 HL154202 The Role of PPARgamma in Th2 cells and Obesity-Associated Asthma. University of California San Francisco Sagar Pradeep Bapat
T32 GM007198 Medical Scientist Training Program THE REGENTS OF THE UNIV. OF CALIF., UNIV. OF CALIF., SAN DIEGO Neil C Chi
R38 HL143581 Enhancing Resident Investigation and Career Advancement in Cardiovascular and Pulmonary Science University of California San Francisco Alison Huang
R01 HL105278 Spatial Regulation of Developmental Gene Expression THE SALK INSTITUTE FOR BIOLOGICAL STUDIES RONALD M EVANS
R01 AI107027 Treg development and function controlled by cis-regulatory circuits THE SALK INSTITUTE FOR BIOLOGICAL STUDIES Ye Zheng
R01 AI151123 The role of BAF related complexes in regulatory T cell development and function THE SALK INSTITUTE FOR BIOLOGICAL STUDIES Ye Zheng
R21 AI154919 A novel role of hypusination in controlling regulatory T cell function THE SALK INSTITUTE FOR BIOLOGICAL STUDIES Ye Zheng
S10 OD023689 BD FACSAria Fusion for Flow Cytometry Core Facility THE SALK INSTITUTE FOR BIOLOGICAL STUDIES Ye Zheng
F30 AI157167 Functional mapping of ex-regulatory T cell phenotypic diversity University of California San Francisco Cody Mowery
Submission date Nov 24, 2021
Last update date Apr 22, 2022
Contact name Alexander Marson
Organization name Gladstone-UCSF Institute of Genomic Immunology
Street address 1650 Owens Street
City San Francisco
State/province CA
ZIP/Postal code 94158
Country USA
 
Platforms (1)
GPL21103 Illumina HiSeq 4000 (Mus musculus)
Samples (8)
GSM5702410 Lesional CD4+ T Cells - Lean Mice
GSM5702411 Lesional CD4+ T Cells - Obese Mice
GSM5702412 Lesional CD4+ T Cells - Control (CD4-Cre) Mice - Lean
Relations
BioProject PRJNA783210
SRA SRP347589

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Supplementary file Size Download File type/resource
GSE189476_Figure3_merged.h5ad.gz 347.6 Mb (ftp)(http) H5AD
GSE189476_Figures1_2_merged.h5ad.gz 366.1 Mb (ftp)(http) H5AD
GSE189476_RAW.tar 78.0 Mb (http)(custom) TAR (of H5)
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Raw data are available in SRA
Processed data are available on Series record
Processed data provided as supplementary file
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