Normalization of obesity-associated insulin resistance through immunotherapy.
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(alpha) repertoires, suggesting antigen-specific expansion. CD4(+) T lymphocyte control of glucose homeostasis is compromised in DIO progression, when VAT accumulates pathogenic interferon-gamma (IFN-gamma)-secreting T helper type 1 (T(H)1) cells, overwhelming static numbers of T(H)2 (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 T(H)2 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 T(H)1 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.
Winer
Shawn
S
Department of Pediatrics & Immunology, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Chan
Yin
Y
Paltser
Geoffrey
G
Truong
Dorothy
D
Tsui
Hubert
H
Bahrami
Jasmine
J
Dorfman
Ruslan
R
Wang
Yongqian
Y
Zielenski
Julian
J
Mastronardi
Fabrizio
F
Maezawa
Yuko
Y
Drucker
Daniel J
DJ
Engleman
Edgar
E
Winer
Daniel
D
Dosch
H-Michael
HM
D000273:Adipose Tissue / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000502:physiology; D002469:Cell Separation; D005947:Glucose / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D006706:Homeostasis / Q000276:immunology; D007167:Immunotherapy / Q000379:methods; D007333:Insulin Resistance / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity / Q000150:complications* / Q000276:immunology / Q000473:pathology / Q000628:therapy*
D018398:Homeodomain Proteins; C064658:RAG-1 protein; D005947:Glucose