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Control of the development of CD8αα+ intestinal intraepithelial lymphocytes by TGF-β

Nature Immunology volume 12, pages 312–319 (2011)Cite this article

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Abstract

The molecular mechanisms that direct the development of TCRαβ+CD8αα+ intestinal intraepithelial lymphocytes (IELs) are not thoroughly understood. Here we show that transforming growth factor-β (TGF-β) controls the development of TCRαβ+CD8αα+ IELs. Mice with either a null mutation in the gene encoding TGF-β1 or T cell–specific deletion of TGF-β receptor I lacked TCRαβ+CD8αα+ IELs, whereas mice with transgenic overexpression of TGF-β1 had a larger population of TCRαβ+CD8αα+ IELs. We observed defective development of the TCRαβ+CD8αα+ IEL thymic precursors (CD4−CD8−TCRαβ+CD5+) in the absence of TGF-β. In addition, we found that TGF-β signaling induced CD8α expression in TCRαβ+CD8αα+ IEL thymic precursors and induced and maintained CD8α expression in peripheral populations of T cells. Our data demonstrate a previously unrecognized role for TGF-β in the development of TCRαβ+CD8αα+ IELs and the expression of CD8α in T cells.

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Figure 1: Mice that lack TGF-β-signaling have fewer TCRαβ+CD8αα+ IELs.
Figure 2: Smad3−/− mice have fewer TCRαβ+CD8αα+ IELs.
Figure 3: Overexpression of TGF-β1 from T cells leads to a larger population of TCRαβ+CD8αα+ IELs.
Figure 4: TGF-β-deficient mice have a smaller population of DN TCRαβ+CD5+ thymocytes.
Figure 5: TGF-β induces CD8α expression on DN TCRαβ+CD5+ thymocytes.
Figure 6: TGF-β is needed to maintain expression of CD8 on peripheral T cells.
Figure 7: TGF-β induces expression of CD8α on peripheral CD4+ T cells in a Smad3-dependent manner.
Figure 8: Expression of Th-POK and Runx3 in CD4+CD8α− and CD4+CD8α+ cells.

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Acknowledgements

We thank G. McGrady and S. Wahl (National Institute of Dental and Craniofacial Research, National Institutes of Health) for Tgfb1−/− mice, and E. Stregevsky and J. Simone for technical assistance. Supported by the Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research and National Cancer Institute, Center for Cancer Research.

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Authors and Affiliations

  1. Mucosal Immunology Unit, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA

    Joanne E Konkel, Takashi Maruyama, Brian F Zamarron, Pin Zhang & WanJun Chen

  2. Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

    Andrea C Carpenter, Yumei Xiong & Remy Bosselut

  3. Functional Genomics Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA

    Bradford E Hall & Ashok B Kulkarni

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Contributions

J.E.K. designed and did experiments, analyzed data and wrote the manuscript; T.M., B.F.Z. and P.Z. did experiments; B.E.H. and A.B.K. provided critical materials; A.C.C. and Y.X. did experiments and provided critical materials, R.B. provided materials and read the manuscript; and W.C. initiated and directed the research, designed experiments and wrote the manuscript.

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Correspondence to WanJun Chen.

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Konkel, J., Maruyama, T., Carpenter, A. et al. Control of the development of CD8αα+ intestinal intraepithelial lymphocytes by TGF-β. Nat Immunol 12, 312–319 (2011). https://doi.org/10.1038/ni.1997

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