Shawn Winer 1 , Yin Chan 1 , Geoffrey Paltser 1 , Dorothy Truong 1 , Hubert Tsui 1 , Jasmine Bahrami 2 , Ruslan Dorfman 4 , Yongqian Wang 4 , Julian Zielenski 4 , Fabrizio Mastronardi 1 , Yuko Maezawa 1 , Daniel Drucker 2 , Edgar Engleman 3 , Daniel Winer 3 , H.-Michael Dosch 1
26 July 2009
Progressive obesity and its associated metabolic syndromes represent a globally growing challenge, yet mechanistic understanding and current therapeutics are unsatisfactory. We discovered that CD4+ T-lymphocytes, resident in visceral adipose tissue (VAT), control insulin-resistance in diet-induced obese (DIO) mice and likely humans. DIO VAT-associated T cells display biased TCR-Vα repertoires suggesting antigen-specific expansion. CD4+ T-lymphocyte control of glucose homeostasis is compromised in DIO when VAT accumulates pathogenic IFNγ-secreting Th1 cells, overwhelming static numbers of Th2 (CD4+GATA-3+) and regulatory Foxp3+ T cells. CD4+ T cell transfer into DIO, lymphocyte-free RAG null mice reversed weight gain and insulin resistance predominately through Th2 cells. Brief systemic treatment with αCD3 antibody or its F(ab′) 2 fragment, restores the Th1/Foxp3+ balance and reverses insulin resistance for months, despite continuing high-fat diet. The progression of obesity-associated metabolic abnormalities is physiologically under CD4+ T cell control, with expansion of adipose tissue-resident T cells that can be manipulated by immunotherapy.