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Regulatory T cells expressing interleukin 10 develop from Foxp3+ and Foxp3− precursor cells in the absence of interleukin 10

Nature Immunology volume 8, pages 931–941 (2007)Cite this article

Abstract

CD4+ regulatory T cells (Treg cells) that produce interleukin 10 (IL-10) are important contributors to immune homeostasis. We generated mice with a 'dual-reporter' system of the genes encoding IL-10 and the transcription factor Foxp3 to track Treg subsets based on coordinate or differential expression of these genes. Secondary lymphoid tissues, lung and liver had enrichment of Foxp3+IL-10− Treg cells, whereas the large and small intestine had enrichment of Foxp3+IL-10+ and Foxp3−IL-10+ Treg cells, respectively. Although negative for Il10 expression, both Foxp3+ and Foxp3− CD4+ thymic precursor cells gave rise to peripheral IL-10+ Treg cells, with only Foxp3− precursor cells giving rise to all Treg subsets. Each Treg subset developed in IL-10-deficient mice, but this was blocked by treatment with antibody to transforming growth factor-β. Thus, Foxp3+ and Foxp3− precursor cells give rise to peripheral IL-10-expressing Treg cells by a mechanism dependent on transforming growth factor-β and independent of IL-10.

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Figure 1: Intestines and associated lymphoid tissues are enriched for IL-10-competent Thy-1.1+CD4+ T cells.
Figure 2: Cytokine phenotypes of Thy-1.1+ and Thy-1.1− CD4+ T cell subpopulations.
Figure 3: Phenotypic and functional analysis of Treg subsets defined by concordant or differential expression of Il10 and Foxp3.
Figure 4: IL-10-competent Treg cells develop extrathymically from both Foxp3+ and Foxp3− thymic precursor cells.
Figure 5: IL-10 is dispensable for the development of IL-10-competent subsets of Foxp3− and Foxp3+ CD4+ T cells.
Figure 6: TGF-β is required for the development of IL-10-competent Treg cells.

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Acknowledgements

We thank D. Chaplin, C. Elson, R. Lorenz, L. Timares, M. Walter and members of the Weaver laboratory for comments and suggestions; C. Song and M. Blake for technical assistance; and N. LeLievre for editorial assistance. Supported by the National Institutes of Health (C.T.W.), the Crohn's and Colitis Foundation of America (C.T.W. and L.E.H.) and the Howard Hughes Medical Institute (A.Y.R.).

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Authors and Affiliations

  1. Department of Pathology, University of Alabama at Birmingham, Birmingham, 35294, Alabama, USA

    Craig L Maynard, Laurie E Harrington, Karen M Janowski, James R Oliver & Casey T Weaver

  2. Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA

    Craig L Maynard & Carlene L Zindl

  3. Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle, 98195, Washington, USA

    Alexander Y Rudensky

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Contributions

C.L.M. did all experiments and collected and analyzed all data with assistance from L.E.H. and C.T.W.; K.M.J. assisted in the development of transgenic mice; J.R.O. provided animal breeding and genotyping technical support; C.L.Z. assisted in the design and execution of immunofluorescence studies; A.Y.R. contributed mice and expertise for some reporter mouse studies; and C.L.M. and C.T.W. wrote the manuscript.

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Correspondence to Casey T Weaver.

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Maynard, C., Harrington, L., Janowski, K. et al. Regulatory T cells expressing interleukin 10 develop from Foxp3+ and Foxp3− precursor cells in the absence of interleukin 10. Nat Immunol 8, 931–941 (2007). https://doi.org/10.1038/ni1504

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