| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Laboratory of Immunology, I. Department of Medicine, and
Department of Toxicology, University of Mainz, Mainz, Germany;
Laboratory of Molecular and Cellular Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan; and
Centro de Investigación del Cáncer, University of Salamanca-Spanish Council for Scientific Research, Salamanca, Spain
We have shown recently that the azathioprine metabolite 6-Thio-GTP causes immunosuppression by blockade of GTPase activation in T lymphocytes. In the present study, we describe a new molecular mechanism by which 6-Thio-GTP blocks GTPase activation. Although 6-Thio-GTP could bind to various small GTPases, it specifically blocked activation of Rac1 and Rac2 but not of closely related Rho family members such as Cdc42 and RhoA in primary T cells upon stimulation with 
CD28 or fibronectin. Binding of 6-Thio-GTP to Rac1 did not suppress Rac effector coupling directly but blocked Vav1 exchange activity upon 6-Thio-GTP hydrolysis, suggesting that 6-Thio-GTP loading leads to accumulation of 6-Thio-GDP-loaded, inactive Rac proteins over time by inhibiting Vav activity. In the absence of apoptosis, blockade of Vav-mediated Rac1 activation led to a blockade of ezrin-radixin-moesin dephosphorylation in primary T cells and suppression of T cell-APC conjugation. Azathioprine-generated 6-Thio-GTP thus prevents the development of an effective immune response via blockade of Vav activity on Rac proteins. These findings provide novel insights into the immunosuppressive effects of azathioprine and suggest that antagonists of the Vav-Rac signaling pathway may be useful for suppression of T cell-dependent pathogenic immune responses.
This article has been cited by other articles:
|
|
 |
|
  J. Wang, L. Cheng, Z. Wondimu, M. Swain, P. Santamaria, and Y. Yang Cutting Edge: CD28 Engagement Releases Antigen-Activated Invariant NKT Cells from the Inhibitory Effects of PD-1 J. Immunol., June 1, 2009; 182(11): 6644 - 6647. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. David, L. Ma, A. Ivetic, A. Takesono, A. J. Ridley, J.-G. Chai, V. L. Tybulewicz, and F. M. Marelli-Berg T-cell receptor- and CD28-induced Vav1 activity is required for the accumulation of primed T cells into antigenic tissue Blood, April 16, 2009; 113(16): 3696 - 3705. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Atreya and M. F Neurath Understanding the delayed onset of action of azathioprine in IBD: are we there yet? Gut, March 1, 2009; 58(3): 325 - 326. [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Bhorade and E. Stern Immunosuppression for Lung Transplantation Proceedings of the ATS, January 15, 2009; 6(1): 47 - 53. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Zeyda, R. Geyeregger, M. Poglitsch, T. Weichhart, G. J. Zlabinger, S. Koyasu, W. H. Horl, T. M. Stulnig, B. Watschinger, and M. D. Saemann Impairment of T cell interactions with antigen-presenting cells by immunosuppressive drugs reveals involvement of calcineurin and NF-{kappa}B in immunological synapse formation J. Leukoc. Biol., January 1, 2007; 81(1): 319 - 327. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Masilamani, C. Nguyen, J. Kabat, F. Borrego, and J. E. Coligan CD94/NKG2A Inhibits NK Cell Activation by Disrupting the Actin Network at the Immunological Synapse J. Immunol., September 15, 2006; 177(6): 3590 - 3596. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
