Glucocorticoids attenuate T cell receptor signaling

被引:100
作者
Van Laethem, F
Baus, E
Smyth, LA
Andris, F
Bex, F
Urbain, J
Kioussis, D
Leo, O
机构
[1] Free Univ Brussels, Physiol Anim Lab, Inst Biol & Med Mol, B-6041 Gosselies, Belgium
[2] Free Univ Brussels, Inst CERIA, Microbiol Lab, B-1070 Brussels, Belgium
[3] Natl Inst Med Res, Div Mol Immunol, London NW7 1AA, England
关键词
T lymphocyte; signal transduction; tyrosine kinases; membrane rafts; glycosphingolipid-enriched microdomains;
D O I
10.1084/jem.193.7.803
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:803 / 814
页数:12
相关论文
共 80 条
  • [41] Role of lipid modifications in targeting proteins to detergent-resistant membrane rafts - Many raft proteins are acylated, while few are prenylated
    Melkonian, KA
    Ostermeyer, AG
    Chen, JZ
    Roth, MG
    Brown, DA
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (06) : 3910 - 3917
  • [42] Engagement of T cell receptor triggers its recruitment to low-density detergent-insoluble membrane domains
    Montixi, C
    Langlet, C
    Bernard, AM
    Thimonier, J
    Dubois, C
    Wurbel, MA
    Chauvin, JP
    Pierres, M
    He, HT
    [J]. EMBO JOURNAL, 1998, 17 (18) : 5334 - 5348
  • [43] Engagement of GPI-linked CD48 contributes to TCR signals and cytoskeletal reorganization: A role for lipid rafts in T cell activation
    Moran, M
    Miceli, MC
    [J]. IMMUNITY, 1998, 9 (06) : 787 - 796
  • [44] GLUCOCORTICOIDS DOWN-REGULATE DENDRITIC CELL-FUNCTION IN-VITRO AND IN-VIVO
    MOSER, M
    DESMEDT, T
    SORNASSE, T
    TIELEMANS, F
    CHENTOUFI, AA
    MURAILLE, E
    VANMECHELEN, C
    URBAIN, J
    LEO, O
    [J]. EUROPEAN JOURNAL OF IMMUNOLOGY, 1995, 25 (10) : 2818 - 2824
  • [45] Characterization of a novel alanine-rich protein located in surface microdomains in Trypanosoma brucei
    Nolan, DP
    Jackson, DG
    Biggs, MJ
    Brabazon, ED
    Pays, A
    Van Laethem, F
    Paturiaux-Hanocq, F
    Elliot, JF
    Voorheis, HP
    Pays, E
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (06) : 4072 - 4080
  • [46] Intrathymic T cell development and selection proceeds normally in the absence of glucocorticoid receptor signaling
    Purton, JF
    Boyd, RL
    Cole, TJ
    Godfrey, DI
    [J]. IMMUNITY, 2000, 13 (02) : 179 - 186
  • [47] Ramirez F, 1996, J IMMUNOL, V156, P2406
  • [48] Exclusion of CD45 inhibits activity of p56(lck) associated with glycolipid-enriched membrane domains
    Rodgers, W
    Rose, JK
    [J]. JOURNAL OF CELL BIOLOGY, 1996, 135 (06) : 1515 - 1523
  • [49] Mature T cell reactivity altered by peptide agonist that induces positive selection
    Sebzda, E
    Kundig, TM
    Thomson, CT
    Aoki, K
    Mak, SY
    Mayer, JP
    Zamborelli, T
    Nathenson, SG
    Ohashi, PS
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 1996, 183 (03) : 1093 - 1104
  • [50] Lipid rafts and signal transduction
    Simons, K
    Toomre, D
    [J]. NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2000, 1 (01) : 31 - 39