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Cloning of a receptor subunit required for signaling by thymic stromal lymphopoietin

Nature Immunology volume 1, pages 59–64 (2000)Cite this article

Abstract

Signaling by type I cytokines involves the formation of receptor homodimers, heterodimers or higher order receptor oligomers. Here we report the cloning of a type I cytokine receptor subunit that is most closely related to the common cytokine receptor γ chain (γc). Binding and crosslinking experiments demonstrate that this protein is the receptor for a recently described interleukin 7 (IL-7)-like factor, thymic stromal lymphopoietin (TSLP). Binding of TSLP to the thymic stromal lymphopoietin receptor (TSLPR) is increased markedly in the presence of the IL-7 receptor α chain (IL-7Rα). IL-7Rα–expressing but not parental 32D cells proliferate in the presence of exogenous TSLP. Moreover, a combination of IL-7Rα and TSLPR is required for TSLP-dependent activation of a STAT5-dependent reporter construct. Thus it is shown that IL-7Rα is a component of both the IL-7 and TSLP receptors, which helps to explain why deletion of the gene that encodes IL-7Rα affects the lymphoid system more severely than deletion of the gene encoding IL-7 does. Cloning of TSLPR should facilitate an understanding of TSLP function and its signaling mechanism.

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Figure 1: A ubiquitously expressed receptor subunit (TSLPR) shares homology with murine γc.
Figure 2: The receptor is ubiquitously expressed.
Figure 3: Homodimerization of TSLPR does not lead to proliferation.
Figure 4: Affinity labeling of TSLPR and IL-7Rα using 125I-TSLP>.
Figure 5: High affinity TSLP receptors—displacement binding experiment.
Figure 6: IL-7Rα is required for proliferation in response to TSLP.
Figure 7: TSLPR is required for signaling by TSLP.

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Acknowledgements

A.P was supported by the Howard Temin Award by NCI (K01 CA 75447). We thank Brad Nelson for providing Kit–β and Kit–γ constructs as well as IL-2 and Xin Liu for providing pMX-IRES-GFP construct. We also thank Peter Munson, CIT, NIH for valuable discussions related to analysis of Scatchard data with the LIGAND computer program. This work was supported in part by grants HL 32262 (H.F.L.), AI44259 (S.F.Z.), CA 26122 (H.B.) and AI44160 (A.F. and S.D.L.) from the National Institutes of Health, and by a grant from Amgen Corporation to H.F.L.

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Authors and Affiliations

  1. Whitehead Institute for Biomedical Research, Cambridge, 02142, MA, USA

    Akhilesh Pandey & Harvey F. Lodish

  2. Department of Pathology, Brigham and Women's Hospital, Boston, 02115, MA, USA

    Akhilesh Pandey

  3. Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, 20892, MD, USA

    Katsutoshi Ozaki, Anne Puel & Warren J. Leonard

  4. Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, 14263, NY, USA

    Heinz Baumann

  5. Department of Immunology, University of Washington, Seattle, 98195, WA, USA

    Steven D. Levin

  6. Department of Biological Structure, University of Washington, Seattle, 98195, WA, USA

    Andrew G. Farr

  7. Virginia Mason Research Center, 1201 9th Ave, Seattle, 98101, WA, USA

    Steven F. Ziegler

  8. Department of Biology, Massachusetts Institute of Technology, Cambridge, 02142, MA, USA

    Harvey F. Lodish

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Correspondence to Warren J. Leonard.

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Pandey, A., Ozaki, K., Baumann, H. et al. Cloning of a receptor subunit required for signaling by thymic stromal lymphopoietin. Nat Immunol 1, 59–64 (2000). https://doi.org/10.1038/76923

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