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 5

Adoptive transfer of diabetes.

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Adoptive transfer of diabetes. (A) Diabetic splenocytes (107 per recipie...
(A) Diabetic splenocytes (107 per recipient) from transgene-negative NOD mice were transferred alone (filled circles, n = 5) or together with an equal number of 2H6 transgene-positive thymocytes (open circles, n = 5), BM cells (open triangles, n = 5), or splenocytes (filled triangles, n = 5). (B) This graph shows the control groups of the experiment in A. Diabetic splenocytes (107 per recipient) from transgene-negative NOD mice were transferred alone (filled circles, n = 5) or together with an equal number of 2H6 transgene-negative thymocytes (open circles, n = 5), BM cells (open triangles, n = 5), or splenocytes (filled triangles, n = 5). (C) Titration of the protective effect of 2H6 transgene-positive splenocytes and cells from PLNs. Diabetic splenocytes (107 per recipient) from transgene-negative NOD mice were transferred alone (filled circles, n = 5) or together with 2H6 transgene-positive splenocytes or PLN cells at different ratios: 2H6 cells/diabetic cells: 0.2:1 (open circles, n = 5), 0.5:1 (filled squares, n = 5), 1:1 (open triangles, n = 6); PLN cells/diabetic cells: 0.25:1 (filled diamonds, n = 4). (D) Diabetic splenocytes (107 per recipient) from BDC2.5 NOD mice were transferred alone (filled circles, n = 4) or together with an equal number of 2H6 transgene-positive splenocytes (open circles, n = 5). All the mice (A–D) were monitored for glycosuria weekly, and the experiments were terminated as indicated unless the mice developed diabetes, which was confirmed by blood glucose measurement (>13.9 mmol/l).