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Transcriptional regulation of the IL-7Rα gene by dexamethasone and IL-7 in primary human CD8 T cells

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Abstract

Interleukin-7 is essential for the development and maintenance of T cells, and the expression of the IL-7 receptor is tightly regulated at every stage of the T cell’s lifespan. In mature CD8 T cells, IL-7 plays important roles in cell survival, peripheral homeostasis, and cytolytic function. The IL-7 receptor alpha-chain (CD127) is expressed at high levels on naïve and memory cells, but it is rapidly downregulated upon IL-7 stimulation. In this study, we illustrate the dynamicity of the CD127 promoter and show that it possesses positive as well as negative regulatory sites involved in upregulating and downregulating CD127 expression, respectively. We cloned the CD127 gene promoter and identified key cis-regulatory elements required for CD127 expression in mature resting primary CD8 T cells. The core promoter necessary for efficient basal transcription is contained within the first 262 bp upstream of the TATA box. Additional positive regulatory elements are located between −1200 and −2406 bp, conferring a further 2- to 4-fold enhancement in gene expression. While transcription of the CD127 gene is increased directly through a glucocorticoid response element located between −2255 and −2269 bp upstream of the TATA box, we identified a suppressive region that lies upstream of 1760 bp from the TATA box, which is likely involved in the IL-7-mediated suppression of CD127 transcription. Finally, we illustrated IL-7 does not bias alternative splicing of CD127 transcripts in primary human CD8 T cells.

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Acknowledgments

This work was supported by a grant from the Canadian Institutes of Health Research (CIHR) (Grant no. 200909HOP-VVP-217823). P.A.M. is the principal recipient of the research grant. J.A.K is a recipient of a Master’s scholarship from the Ontario HIV Treatment Network (OHTN). F.M.G. and S.M.S are recipients of CIHR doctoral scholarships and E.M.F. is a recipient of a postdoctoral fellowship from OHTN. P.A.M. is supported in part by a mid-career salary award from the Dept. of Medicine, University of Ottawa. We would also like to thank the volunteers who donated blood samples for this study.

Authors’ contributions

JAK carried out the cloning, transfection, and luciferase assays; flow cytometry; the Western blot analysis and qPCR work (Figs. 1, 2, 3, 4, 5, 6, and 8); and wrote the manuscript. FMG carried out the Western blot analysis and participated in the promoter map** analysis, qPCR, transfection and luciferase assays (Figs. 1a, 7, and 9a, b), and co-wrote the manuscript. EMF participated in flow cytometry (Fig. 9c). S.M.S participated in the cloning work. PP participated in transfection and luciferase assay (Fig. 7). PAM designed the research, analyzed and interpreted data, and co-wrote the manuscript.

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    1. Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, K1H8L6, Canada

      Juzer A. Kakal, Feras M. Ghazawi, Elliott M. Faller, Scott M. Sugden, Parmvir Parmar & Paul A. MacPherson

    2. Departments of Medicine, and Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, K1H8M5, Canada

      Juzer A. Kakal, Scott M. Sugden & Paul A. MacPherson

    3. Division of Infectious Diseases, The Ottawa Hospital, General Campus, Box 223, 501 Smyth Road, Ottawa, Ontario, K1H 8L6, Canada

      Paul A. MacPherson

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    1. Juzer A. Kakal
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    Juzer A. Kakal and Feras M. Ghazawi contributed equally to this study.

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    Kakal, J.A., Ghazawi, F.M., Faller, E.M. et al. Transcriptional regulation of the IL-7Rα gene by dexamethasone and IL-7 in primary human CD8 T cells. Immunogenetics 69, 13–27 (2017). https://doi.org/10.1007/s00251-016-0948-4

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