Winer Shawn, Chan Yin, Paltser Geoffrey, Truong Dorothy, Tsui Hubert, Bahrami Jasmine, Dorfman Ruslan, Wang Yongqian, Zielenski Julian, Mastronardi Fabrizio, Maezawa Yuko, Drucker Daniel J, Engleman Edgar, Winer Daniel, Dosch H-Michael
Department of Pediatrics & Immunology, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Nat Med. 2009 Aug;15(8):921-9. doi: 10.1038/nm.2001. Epub 2009 Jul 26.
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.
肥胖及其相关的代谢综合征是一个日益严峻的全球性挑战，但对这种病理状况的机制理解以及当前的治疗方法都不尽人意。我们发现，驻留在内脏脂肪组织（VAT）中的CD4(+) T淋巴细胞可控制饮食诱导肥胖（DIO）小鼠的胰岛素抵抗。对人体组织的分析表明，类似的过程可能也会在人类中发生。DIO VAT相关的T细胞显示出严重偏向的T细胞受体V(α)库，提示抗原特异性扩增。在DIO进展过程中，当VAT中积累了分泌致病性干扰素-γ（IFN-γ）的1型辅助性T细胞（T(H)1），超过了静态数量的T(H)2（CD4(+)GATA结合蛋白-3（GATA-3）(+)）和调节性叉头框P3（Foxp3）(+) T细胞时，CD4(+) T淋巴细胞对葡萄糖稳态的控制就会受到损害。将CD4(+)（而非CD8(+)）T细胞转移到无淋巴细胞的Rag1基因敲除DIO小鼠中，可逆转体重增加和胰岛素抵抗，主要是通过T(H)2细胞实现的。在肥胖的野生型和ob/ob（瘦素缺乏）小鼠中，用CD3特异性抗体或其F(ab')(2)片段进行短暂治疗，可减少T(H)1细胞相对于Foxp3(+)细胞的优势，尽管继续给予高脂饮食，但胰岛素抵抗仍可逆转数月。我们的数据表明，肥胖相关代谢异常的进展受CD4(+) T细胞的病理生理控制。随着肥胖和致病性VAT T细胞的增加，这种控制最终失效，但可通过免疫疗法成功逆转。
