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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

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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 1

2H6 TCR transgene expression and phenotypic analysis of the transgenic mice.

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2H6 TCR transgene expression and phenotypic analysis of the transgenic m...
(A) Expression of 2H6 TCR transgene. Thymocytes, splenocytes, and lymphocytes isolated from pancreatic and axillary lymph nodes (PLNs and ALNs, respectively) of 2H6 TCR transgenic (line 50) and nontransgenic NOD mice were stained with anti-Vβ14, anti-CD4, anti-CD8, and a cocktail of anti-Vα mAbs and analyzed by flow cytometry. The numbers in quadrants represent the percentage of positive cells among the total cells analyzed. (B) 2H6 transgenic T cells express an effector/memory–like phenotype. Lymphocytes isolated from spleen of nontransgenic (top panel) and 2H6 TCR transgenic (bottom panel) NOD mice were stained with CD4, CD45RB, CD62L, and CD44. The cells were then analyzed by flow cytometry. (C) CD25 expression of splenic CD4+ T cells in 2H6 TCR transgene-positive and -negative NOD mice. Splenocytes were harvested from both types of mice and stained with CD4 and CD25 with and without anti-CD3 stimulation. The numbers in the top right quadrants represent the percentage of positive cells among the total cells analyzed.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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