The Journal of Experimental Medicine
VeriKine-HS Human Interferon-Beta Serum
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Published online 2 April 2001.
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© The Rockefeller University Press, 0022-1007/2001/4/803/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 7, April 2, 2001 803-814

Original Article

Glucocorticoids Attenuate T Cell Receptor Signaling

François Van Laethema, Erika Bausa, Lesley A. Smythc, Fabienne Andrisa, Françoise Bexb, Jacques Urbaina, Dimitris Kioussisc, and Oberdan Leoa

a Laboratoire de Physiologie Animale, Institut de Biologie et de Médecine Moléculaires, Université Libre de Bruxelles, 6041 Gosselies, Belgium
b Laboratoire de Microbiologie, Institut CERIA, Université Libre de Bruxelles, 1070 Bruxelles, Belgium
c Division of Molecular Immunology, The National Institute of Medical Research, London NW7 1AA, United Kingdom
Laboratoire de Physiologie Animale, Université Libre de Bruxelles, Rue des Prof. Jeener et Brachet 12, B-6041 Gosselies, Belgium.32-2650-986032-2650-9877

oleo{at}dbm.ulb.ac.be

Glucocorticoids (GCs) affect peripheral immune responses by inhibiting T cell immunity at several stages of the activation cascade, causing impaired cytokine production and effector function. The recent demonstration that the thymic epithelium and possibly thymocytes themselves produce steroids suggests that endogenous GCs also play a role in the control of T cell development. As both peripheral responsiveness and thymic differentiation appear to be regulated by the quantity and quality of intracellular signals issued by antigen–major histocompatibility complex-engaged T cell receptor (TCR) complexes, we investigated the effects of GCs on the signaling properties of T cells stimulated by anti-CD3 monoclonal antibodies or agonist peptides. We demonstrate in this work that dexamethasone, a synthetic GC, inhibits the early signaling events initiated upon TCR ligation, such as tyrosine phosphorylation of several TCR-associated substrates including the {zeta} chain, the ZAP70 kinase, and the transmembrane adapter molecule linker for activation of T cells. Hypophosphorylation was not a consequence of reduced kinase activity of src protein tyrosine kinases, but was correlated with an altered- membrane compartmentalization of these molecules. These observations indicate that in addition to their well-described ability to interfere with the transcription of molecules involved in peripheral responses, GCs inhibit T cell activation by affecting the early phosphorylating events induced after TCR ligation.

Key Words: T lymphocyte • signal transduction • tyrosine kinases • membrane rafts • glycosphingolipid-enriched microdomains

Abbreviations used in this paper: β2m, β2-microglobulin; DEX, dexamethasone; GAG, glycosaminoglycan; GC, glucocorticoid; GEM, glycolipid-enriched membrane microdomain; GPI, glycosyl phosphatidylinositol; HRP, horseradish peroxidase; ITAM, immunoreceptor tyrosine-based activation motif; LAT, linker for activation of T cells; MES, morpholinoethane sulfonic acid; PLC, phospholipase C; PTK, protein tyrosine kinase; Rag, recombination activating gene.

© 2001 The Rockefeller University Press


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