TGF-β signaling is required for the function of insulin-reactive T regulatory cells
Wei Du, … , Robert Sherwin, Li Wen
Wei Du, … , Robert Sherwin, Li Wen
Published May 1, 2006
Citation Information: J Clin Invest. 2006;116(5):1360-1370. https://doi.org/10.1172/JCI27030.
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Research Article Autoimmunity

TGF-β signaling is required for the function of insulin-reactive T regulatory cells

Abstract

We have previously isolated insulin-reactive Tregs from diabetic NOD mice designated 2H6, from which TCR transgenic mice were generated. The T cells from these 2H6 transgenic mice recognize insulin but have suppressive properties in vitro. They protect NOD mice in vivo from spontaneous development of diabetes and adoptive transfer of disease caused by polyclonal diabetogenic spleen cells as well as the highly diabetogenic monoclonal BDC2.5 TCR transgenic T cells that recognize an islet granule antigen. Using cells from both NOD and BDC2.5 mice that express a dominant-negative TGF-β receptor type II (TGF-βDNRII), we show that 2H6 T cells protected from disease by producing TGF-β and that the ability of the target diabetogenic T cells to respond to TGF-β was crucial. We further demonstrate that TGF-β signaling in 2H6 cells was important for their protective properties, as 2H6 cells were unable to protect from adoptive transfer–induced diabetes if they were unable to respond to TGF-β. Thus, our data demonstrate that insulin-specific regulatory cells protect from diabetes by virtue of their production of TGF-β1 that acts in an autocrine manner to maintain their regulatory function and acts in a paracrine manner on the target cells.

Authors

Wei Du, F. Susan Wong, Ming O. Li, Jian Peng, Hao Qi, Richard A. Flavell, Robert Sherwin, Li Wen

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Figure 4

Natural history of diabetes development and islet histology.

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Natural history of diabetes development and islet histology. (A) Inciden...
(A) Incidence of diabetes. 2H6 TCR transgene-positive and -negative NOD mice (both sexes) were observed for diabetes development over 7 months. All the mice were monitored for glycosuria weekly, and diabetes was confirmed by blood glucose measurement (>13.9 mmol/l). (B) Histology. Paraffin sections of pancreas were made, stained with H&E, and examined for insulitis and/or islet destruction. The magnification for the transgene-negative section is ×100. The magnification for the transgene-positive sections is ×40. (C) Insulitis score. One hundred to 240 islets were analyzed microscopically for insulitis and scored as grade 0 (clean islets, no infiltration), grade I (peri-insulitis), grade II (mild insulitis), grade III (severe insulitis), and grade IV (complete destruction by infiltrating cells). (D) Histology. Paraffin sections of pancreas from 2H6.scid mice were prepared and stained with H&E. The sections were compared with nontransgenic NOD.scid islets. The magnification is ×100.