| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
*
Department of Microbiology and Molecular Genetics, New England Regional Primate Research Center, Harvard Medical School, Southborough, MA 01772; and
Department of Pediatrics and Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655
The molecular basis of X-linked lymphoproliferative (XLP) disease
has been attributed to mutations in the signaling lymphocytic
activation molecule-associated protein (SAP), an src homology 2
domain-containing intracellular signaling molecule known to interact
with the lymphocyte-activating surface receptors signaling lymphocytic
activation molecule and 2B4. To investigate the effect of SAP defects
on TCR signal transduction, herpesvirus saimiri-immortalized CD4 Th
cells from XLP patients and normal healthy individuals were examined
for their response to TCR stimulation. CD4 T cells of XLP patients
displayed elevated levels of tyrosine phosphorylation compared with CD4
T cells from healthy individuals. In addition, downstream
serine/threonine kinases are constitutively active in CD4 T cells of
XLP patients. In contrast, TCR-mediated activation of Akt,
c-Jun-NH2-terminal kinases, and extracellular
signal-regulated kinases in XLP CD4 T cells was transient and rapidly
diminished when compared with that in control CD4 T cells.
Consequently, XLP CD4 T cells exhibited severe defects in up-regulation
of IL-2 and IFN-
cytokine production upon TCR stimulation and in
MLRs. Finally, SAP specifically interacted with a 75-kDa
tyrosine-phosphorylated protein upon TCR stimulation. These results
demonstrate that CD4 T cells from XLP patients exhibit aberrant TCR
signal transduction and that the defect in SAP function is likely
responsible for this phenotype.
This article has been cited by other articles:
|
|
 |
|
  N. J. Hare, C. S. Ma, F. Alvaro, K. E. Nichols, and S. G. Tangye Missense mutations in SH2D1A identified in patients with X-linked lymphoproliferative disease differentially affect the expression and function of SAP Int. Immunol., July 1, 2006; 18(7): 1055 - 1065. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-C. Chuang, J.-D. Lay, W.-C. Hsieh, H.-C. Wang, Y. Chang, S.-E. Chuang, and I.-J. Su Epstein-Barr virus LMP1 inhibits the expression of SAP gene and upregulates Th1 cytokines in the pathogenesis of hemophagocytic syndrome Blood, November 1, 2005; 106(9): 3090 - 3096. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Chen, A. K. Tai, M. Lin, F. Chang, C. Terhorst, and B. T. Huber Signaling Lymphocyte Activation Molecule-Associated Protein Is a Negative Regulator of the CD8 T Cell Response in Mice J. Immunol., August 15, 2005; 175(4): 2212 - 2218. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Dupre, G. Andolfi, S. G. Tangye, R. Clementi, F. Locatelli, M. Arico, A. Aiuti, and M.-G. Roncarolo SAP controls the cytolytic activity of CD8+ T cells against EBV-infected cells Blood, June 1, 2005; 105(11): 4383 - 4389. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Martin-Fernandez, J. A. Cabanillas, M. Rivero-Carmena, E. Lacasa, J. Pardo, A. Anel, P. R. Ramirez-Duque, F. Merino, C. Rodriguez-Gallego, and J. R. Regueiro Herpesvirus saimiri-transformed CD8+ T cells as a tool to study Chediak-Higashi syndrome cytolytic lymphocytes J. Leukoc. Biol., May 1, 2005; 77(5): 661 - 668. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Sharifi, J. C. Sinclair, K. C. Gilmour, P. D. Arkwright, C. Kinnon, A. J. Thrasher, and H. B. Gaspar SAP mediates specific cytotoxic T-cell functions in X-linked lymphoproliferative disease Blood, May 15, 2004; 103(10): 3821 - 3827. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Simarro, A. Lanyi, D. Howie, F. Poy, J. Bruggeman, M. Choi, J. Sumegi, M. J. Eck, and C. Terhorst SAP increases FynT kinase activity and is required for phosphorylation of SLAM and Ly9 Int. Immunol., May 1, 2004; 16(5): 727 - 736. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Sorokina, J. J. Merlo Jr., and A. Y. Tsygankov Molecular Mechanisms of the Effect of Herpesvirus saimiri Protein StpC on the Signaling Pathway Leading to NF-{kappa}B Activation J. Biol. Chem., April 2, 2004; 279(14): 13469 - 13477. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Sanzone, M. Zeyda, M. D. Saemann, M. Soncini, W. Holter, G. Fritsch, W. Knapp, F. Candotti, T. M. Stulnig, and O. Parolini SLAM-associated Protein Deficiency Causes Imbalanced Early Signal Transduction and Blocks Downstream Activation in T Cells from X-linked Lymphoproliferative Disease Patients J. Biol. Chem., August 8, 2003; 278(32): 29593 - 29599. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Shinozaki, H. Kanegane, H. Matsukura, R. Sumazaki, M. Tsuchida, M. Makita, Y. Kimoto, R. Kanai, K. Tsumura, T. Kondoh, et al. Activation-dependent T cell expression of the X-linked lymphoproliferative disease gene product SLAM-associated protein and its assessment for patient detection Int. Immunol., October 1, 2002; 14(10): 1215 - 1223. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
