Article abstract
Nature Medicine 15, 921 - 929 (2009)
Published online: 26 July 2009 | doi:10.1038/nm.2001
Normalization of obesity-associated insulin resistance through immunotherapy
Shawn Winer1,5, Yin Chan1,5, Geoffrey Paltser1, Dorothy Truong1, Hubert Tsui1, Jasmine Bahrami2, Ruslan Dorfman4, Yongqian Wang4, Julian Zielenski4, Fabrizio Mastronardi1, Yuko Maezawa1, Daniel J Drucker2, Edgar Engleman3, Daniel Winer3 & H.-Michael Dosch1
Abstract
Obesity and its associated metabolic syndromes represent a growing global challenge, yet mechanistic understanding of this pathology and current therapeutics are unsatisfactory. We discovered that CD4+ T lymphocytes, resident in visceral adipose tissue (VAT), control insulin resistance in mice with diet-induced obesity (DIO). Analyses of human tissue suggest that a similar process may also occur in humans. DIO VAT-associated T cells show severely biased T cell receptor V
repertoires, suggesting antigen-specific expansion. CD4+ T lymphocyte control of glucose homeostasis is compromised in DIO progression, when VAT accumulates pathogenic interferon-
(IFN-)-secreting T helper type 1 (TH1) cells, overwhelming static numbers of TH2 (CD4+GATA-binding protein-3 (GATA-3)+) and regulatory forkhead box P3 (Foxp3)+ T cells. CD4+ (but not CD8+) T cell transfer into lymphocyte-free Rag1-null DIO mice reversed weight gain and insulin resistance, predominantly through TH2 cells. In obese WT and ob/ob (leptin-deficient) mice, brief treatment with CD3-specific antibody or its F(ab')2 fragment, reduces the predominance of TH1 cells over Foxp3+ cells, reversing insulin resistance for months, despite continuation of a high-fat diet. Our data suggest that the progression of obesity-associated metabolic abnormalities is under the pathophysiological control of CD4+ T cells. The eventual failure of this control, with expanding adiposity and pathogenic VAT T cells, can successfully be reversed by immunotherapy.
- Neuroscience & Mental Health Program, Research Institute, The Hospital for Sick Children, University of Toronto Departments of Pediatrics & Immunology, Toronto, Ontario, Canada.
- Department of Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
- Department of Pathology, Stanford University School of Medicine, Palo Alto, California, USA.
- Program in Genetics and Genomic Biology, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
- These authors contributed equally to this work.
Correspondence to: H.-Michael Dosch1 e-mail: michael.dosch@me.com
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