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 3

2H6 contact–dependent and –independent suppression of BDC2.

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2H6 contact–dependent and –independent suppression of BDC2. cells in re...
cells in response to the mimotope peptide. (A and B) Splenocytes from BDC2.5 transgenic NOD mice were cultured with the mimotope peptide in the presence or absence of 2H6 cells. The ratio of BDC2.5 cells to 2H6 cells was 2:1. The same culture was also performed with 2H6 cells in Transwells (0.4 μm) to prevent the cell contact between 2H6 and BDC2.5 cells without preventing the flow of soluble factor(s). Splenocytes from 2H6 transgene-negative NOD mice were used as controls in the coculture system at the same ratio. A represents 1 of 3 experiments. To confirm that suppression was indeed mediated by 2H6 cells, the experiments were also repeated using 2H6 cells from 2H6.scid mice and purified CD4+ T cells from NOD mice as controls at the same ratio as in A. B shows 1 of the 2 such experiments. Results are illustrated as Δ cpm = proliferation with mimotope peptide – proliferation with medium for each of the conditions. (C) The suppression by 2H6 cells is completely abolished if 2H6 cells express a dominant-negative TGF-β receptor (TGF-βDNRII) (designated 2H6 DNR T cells). The abolition was seen in both coculture and Transwell culture conditions. C represents 1 of 2 experiments, and the ratio of BDC2.5 T cells to 2H6 DNR cells was also 2:1 as for the experiment shown in A and B.