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Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis

Abstract

Regulatory T cells (Treg cells) that express the transcription factor Foxp3 suppress the activity of other cells. Here we show that interleukin 10 (IL-10) produced by CD11b+ myeloid cells in recombination-activating gene 1–deficient (Rag1−/−) recipient mice was needed to prevent the colitis induced by transferred CD4+CD45RBhi T cells. In Il10−/−Rag1−/− mice, Treg cells failed to maintain Foxp3 expression and regulatory activity. The loss of Foxp3 expression occurred only in recipients with colitis, which indicates that the requirement for IL-10 is manifested in the presence of inflammation. IL-10 receptor–deficient (Il10rb−/−) Treg cells also failed to maintain Foxp3 expression, which suggested that host IL-10 acted directly on the Treg cells. Our data indicate that IL-10 released from myeloid cells acts in a paracrine manner on Treg cells to maintain Foxp3 expression.

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Figure 1: IL-10-deficient Treg cells prevent colitis.
Figure 2: Rag1−/− host IL-10 is required for Treg cell function.
Figure 3: Foxp3 is downregulated in Il10−/−Rag1−/− recipients.
Figure 4: Loss of function by Treg cells from Il10−/−Rag1−/− recipients.
Figure 5: Il10rb−/− Treg cells fail to prevent colitis.
Figure 6: Foxp3 is lost 'preferentially' by Il10rb−/− Treg cells in mice with colitis.
Figure 7: Kinetics of IL-10 expression by Treg cells and host cells.
Figure 8: IL-10-producing CD11b+ myeloid cells prevent the downregulation of Foxp3.

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Acknowledgements

We thank M. Steinberg and D. Mucida for critical reading of this manuscript, members of the Kronenberg and Cheroutre laboratories for discussions; Y. Wang-Zhu for genotyping mice; L. Fernandez, C. Kim and B. Sears for assistance with cell sorting; P. Allen (Washington University) for Il10rb−/− mice; and A. Rudensky (Memorial Sloan Kettering Cancer Center) for Foxp3gfp mice. Supported by US National Institutes of Health (PO1 DK46763 to M.K., RO1 AI057992 to C.L.K. and RO1 AI50265 to H.C.) and the Crohn's & Colitis Foundation of America (M.K. and M.M.).

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M.M. and M.K. designed experiments; M.M. did experiments; O.T. did histology and helped with cell preparation; R.M. and C.L.K. generated and provided IL-10 reporter mice; G.K. and H.C. helped with critical advice and discussions throughout; and M.M. and M.K. wrote the manuscript.

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Correspondence to Mitchell Kronenberg.

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Murai, M., Turovskaya, O., Kim, G. et al. Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat Immunol 10, 1178–1184 (2009). https://doi.org/10.1038/ni.1791

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