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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 Vα repertoires, suggesting antigen-specific expansion. CD4+ T lymphocyte control of glucose homeostasis is compromised in DIO progression, when VAT accumulates pathogenic interferon-γ (IFN-γ)-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.

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Acknowledgements

These studies were supported by the Canadian Institutes of Health Research. Y.C. and G.P. were recipients of scholarships from the Canadian Institutes of Health Research and the Banting & Best Foundation. Antibodies to OT2 TCR heavy and light chain were a gift from D. Philpott (University of Toronto).

Author information

Author notes

    • Shawn Winer
    •  & Yin Chan

    These authors contributed equally to this work.

Affiliations

  1. Neuroscience & Mental Health Program, Research Institute, The Hospital for Sick Children, University of Toronto Departments of Pediatrics & Immunology, Toronto, Ontario, Canada.

    • Shawn Winer
    • , Yin Chan
    • , Geoffrey Paltser
    • , Dorothy Truong
    • , Hubert Tsui
    • , Fabrizio Mastronardi
    • , Yuko Maezawa
    •  & H.-Michael Dosch
  2. Department of Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.

    • Jasmine Bahrami
    •  & Daniel J Drucker
  3. Department of Pathology, Stanford University School of Medicine, Palo Alto, California, USA.

    • Edgar Engleman
    •  & Daniel Winer
  4. Program in Genetics and Genomic Biology, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

    • Ruslan Dorfman
    • , Yongqian Wang
    •  & Julian Zielenski

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Contributions

S.W. and Y.C. conceived of the study and carried out the bulk of the experiments. G.P., D.T., H.T. and Y.M. performed a number of mouse experiments. R.D., Y.W. and J.Z. provided much of the TCR material, F.M. helped with adipocyte analysis, J.B. and D.D. provided metabolic studies, E.E. and D.W. generated the bulk of human data, S.W. and H.-M.D. wrote the manuscript, and H.-M.D. financed and supervised the project and the peer review process.

Competing interests

H.M.D. holds shares in Afference Therapeutics, Inc., a start-up biotech corporation.

Corresponding author

Correspondence to H.-Michael Dosch.

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DOI

https://doi.org/10.1038/nm.2001