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Expression by IL-7 and TCR Signaling1
* Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands and
Department of Internal Medicine, Division of Nephrology, Academic Medical Center, Amsterdam, The Netherlands
IL-7R
is essential for the development and homeostatic maintenance of mature T cells. Studies in humans and mice have shown that IL-7R expression is reduced by its cognate cytokine, IL-7, and Ag, suggesting that active regulation of IL-7 responsiveness is necessary to balance T cell numbers. We show that IL-7- or TCR/CD28-mediated signaling induced a rapid down-regulation of IL-7R expression on naive T cells on the mRNA and protein level, with a mild (10-fold) or strong (50-fold) gene suppression, respectively. In both situations, the down-regulation of IL-7R was blocked by cyclohexamide and actinomycin D, indicating the involvement of an active mechanism dependent on new transcription and protein synthesis. Upon IL-7 withdrawal, IL-7R mRNA and surface protein reappeared in a transcription-dependent manner within 7 h. Yet, IL-7R was hardly re-expressed during the same period after TCR/CD28-activation. Likewise, T cells that were activated through CMV in vivo did not re-express IL-7R after in vitro culture. Functionally, IL-7-induced down-regulation of IL-7R did not hinder the responsiveness of naive T cells to IL-7. Conversely, down-regulation of IL-7R on TCR/CD28-activated cells limited IL-7 responsiveness. Strikingly, ectopic expression of IL-7R cells on TCR/CD28-activated cells conferred a selective advantage in the response to IL-7. In conclusion, our data show that IL-7- and TCR/CD28-mediated signaling differentially regulate IL-7R expression on human T cells with a transient and chronic effect, respectively. The stringent and active regulation of IL-7R may constitute a homeostatic mechanism to curtail unwarranted T cell expansion.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was funded by VICI and research (912-04-032) grants both from Netherlands Organization for Scientific Research (NWO) to R.A.W. van Lier.
2 Current address: Unite des Cytokines et Developpment Lymphoide, Institut Pasteur, Paris, France.
3 Current address: Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037.
4 Address correspondence and reprint requests to Dr. R.A.W. van Lier, Academic Medical Center, Laboratory for Experimental Immunology K0-146, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail address: r.vanlier{at}amc.uva.nl
5 Abbreviations used in this paper: CHX, cyclohexamide; Act D, actinomycin D; IRES, internal ribosomal entry site; O/N, overnight; MFI, mean fluorescence intensity; TSLP, thymic stromal lymphopoietin.
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  T. Rose, O. Lambotte, C. Pallier, J.-F. Delfraissy, and J.-H. Colle Identification and Biochemical Characterization of Human Plasma Soluble IL-7R: Lower Concentrations in HIV-1-Infected Patients J. Immunol., June 15, 2009; 182(12): 7389 - 7397. [Abstract] [Full Text] [PDF]
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