期刊
NATURE
卷 604, 期 7905, 页码 337-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41586-022-04536-0
关键词
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资金
- U.S. National Institutes of Health (NIH) [F30 DK096828, T32 GM007198, R38 HL143581, K38 HL154202, P30GM127211, HL147835, HL105278, CA014195]
- KAIST [N11210257]
- National Research Foundation of Korea [2017K1A1A2013124, 2021R1A2C200757311]
- Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Science and ICT [NRF-2017R1A2B3006406]
- NIH [U01AI52038, R01AI53185, R01AR076082, R01DK121760, R37AI052453]
- American Heart Association grant [16BGIA27790079]
- VA BLR&D Career Development Award [1IK2BX001313]
- NOMIS Foundation-Science of Health
- HHMI
- Foundation Leducq
- Don and Lorraine Freeberg Foundation
- Larry L. Hillblom foundation
- David C. Copley Foundation
- NOMIS Foundation
- Crohn's and Colitis Foundation
- Leona M. and Harry B. Helmsley Charitable Trust
- National Institute of Health [R01-AI107027, R01-AI1511123, R21-AI154919, S10-OD023689, NCI CCSG P30-014195]
- Cancer Research Institute (CRI) Lloyd J. Old STAR grant
- Innovative Genomics Institute (IGI)
- Simons Foundation
- Parker Institute for Cancer Immunotherapy (PICI)
- National Cancer Institute [CA014195]
- James B. Pendleton Charitable Trust
- UCSF Parnassus Flow Cytometry Core by the Diabetes Research Center grant from the National Institutes of Health [P30 DK063720]
- National Institute of Environmental Health Sciences of the National Institutes of Health [P42ES010337]
- National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health [R01DK057978, R01DK120480]
- National Research Foundation of Korea [2017K1A1A2013124] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Obesity can disrupt immune responses and alter the effectiveness of immunotherapies by changing T cell immune reactions and decreasing the activity of PPAR gamma in Th2 cells.
Decades of work have elucidated cytokine signalling 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. Recent evidence indicates that obesity and metabolic disease can also influence the immune system(1-7), although the mechanisms and effects on immunotherapy outcomes remain largely unknown. Here, using two models of atopic dermatitis, we show that lean and obese mice mount markedly different immune responses. Obesity converted the classical type 2 T helper (T(H)2)-predominant disease associated with atopic dermatitis to a more severe disease with prominent T(H)17 inflammation. We also observed divergent responses to biologic therapies targeting T(H)2 cytokines, which robustly protected lean mice but exacerbated disease in obese mice. Single-cell RNA sequencing coupled with genome-wide binding analyses revealed decreased activity of nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR gamma) in T(H)2 cells from obese mice relative to lean mice. Conditional ablation of PPAR gamma in T cells revealed that PPAR gamma is required to focus the in vivo T-H response towards a T(H)2-predominant state and prevent aberrant non-T(H)2 inflammation. Treatment of obese mice with a small-molecule PPAR gamma agonist limited development of T(H)17 pathology and unlocked therapeutic responsiveness to targeted anti-T(H)2 biologic therapies. These studies reveal the effects of obesity on immunological disease and suggest a precision medicine approach to target the immune dysregulation caused by obesity.
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