Differential regulation of human IL-7 receptor alpha expression by IL-7 and TCR signaling.
IL-7Ralpha is essential for the development and homeostatic maintenance of mature T cells. Studies in humans and mice have shown that IL-7Ralpha 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-7Ralpha 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-7Ralpha 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-7Ralpha mRNA and surface protein reappeared in a transcription-dependent manner within 7 h. Yet, IL-7Ralpha 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-7Ralpha after in vitro culture. Functionally, IL-7-induced down-regulation of IL-7Ralpha did not hinder the responsiveness of naive T cells to IL-7. Conversely, down-regulation of IL-7Ralpha on TCR/CD28-activated cells limited IL-7 responsiveness. Strikingly, ectopic expression of IL-7Ralpha 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-7Ralpha expression on human T cells with a transient and chronic effect, respectively. The stringent and active regulation of IL-7Ralpha may constitute a homeostatic mechanism to curtail unwarranted T cell expansion.
Alves
Nuno L
NL
Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands.
van Leeuwen
Ester M M
EM
Derks
Ingrid A M
IA
van Lier
René A W
RA
D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D015851:Interleukin-7 / Q000276:immunology / Q000378:metabolism*; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D020395:Receptors, Interleukin-7 / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D018106:CD28 Antigens; D016207:Cytokines; D015851:Interleukin-7; D011948:Receptors, Antigen, T-Cell; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain