International Immunology, Vol. 11, No. 12, 1999-2014,
December 1999
© 1999 Japanese Society for Immunology
The tyrosine phosphatase SHP-1 influences thymocyte selection by setting TCR signaling thresholds
Department of Microbiology, University of Virginia, HSC, Box 441, 1300 Jefferson Park Avenue, Charlottesville, VA 22908, USA
1 Cancer Biology Program, Division of Hematology–Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
Correspondence to: U. Lorenz
Modulation of the strength of signals from the TCR determines the outcome of positive and negative selection in thymocyte development. Previous studies have demonstrated that SHP-1 plays a role in determining signal strength from the TCR. Here, we have taken a genetic approach to test whether SHP-1 plays a role in T cell selection in the thymus. Experiments in which a dominant negative mutant of SHP-1 was expressed in the BYDP hybridoma cell line confirmed that SHP-1 regulated TCR signaling in a cell-autonomous manner and suggested that Lck is one of its targets. To examine the role of SHP-1 in T cell development, we crossed the ovalbumin-specific DO11.10 TCR transgene onto the motheaten background, which lacks SHP-1 expression. Analysis of the progeny of these crosses provided evidence that SHP-1 regulates thymocyte selection: (i) flow cytometric analyses revealed alterations in the percentages of thymocyte subpopulations in the me/me background; (ii) ex vivo deletion experiments demonstrated that me/me:Tg thymocytes undergo negative selection at lower concentrations of OVA peptide compared to +/+:Tg thymocytes; and (iii) ex vivo proliferation analyses indicated that me/me:Tg thymocytes were hyper-sensitive to stimulation by the specific OVA peptide. Our observation that the absence of SHP-1 leads to altered selection of TCR transgenic thymocytes demonstrates that SHP-1 regulates the strength of TCR-mediated signals in vivo and, in turn, helps to set the threshold for thymocyte selection.
Keywords: DO11.10 TCR, protein kinases/phosphatases, signal transduction, T lymphocytes, TCR, transgenic mice
Transmitting editor: A. Singer
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Gatzka, R. H. Newton, and C. M. Walsh Altered Thymic Selection and Increased Autoimmunity Caused by Ectopic Expression of DRAK2 during T Cell Development J. Immunol., July 1, 2009; 183(1): 285 - 297. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. J. Schnell, N. Alberts-Grill, and B. D. Evavold CD8+ T Cell Responses to a Viral Escape Mutant Epitope: Active Suppression via Altered SHP-1 Activity J. Immunol., February 15, 2009; 182(4): 1829 - 1835. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. A. Wasserman, C. D. Beal, Y. Zhang, N. Jiang, C. Zhu, and B. D. Evavold MHC Variant Peptide-Mediated Anergy of Encephalitogenic T Cells Requires SHP-1 J. Immunol., November 15, 2008; 181(10): 6843 - 6849. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. U. A. Mollah, S. Pai, C. Moore, B. J. O'Sullivan, M. J. Harrison, J. Peng, K. Phillips, J. B. Prins, J. Cardinal, and R. Thomas Abnormal NF-{kappa}B Function Characterizes Human Type 1 Diabetes Dendritic Cells and Monocytes J. Immunol., March 1, 2008; 180(5): 3166 - 3175. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. G. Sathish, G. Dolton, F. G. LeRoy, and R. J. Matthews Loss of Src Homology Region 2 Domain-Containing Protein Tyrosine Phosphatase-1 Increases CD8+ T Cell-APC Conjugate Formation and Is Associated with Enhanced In Vivo CTL Function J. Immunol., January 1, 2007; 178(1): 330 - 337. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. V. Nguyen, Y. Ke, E. E. Zhang, and G.-S. Feng Conditional Deletion of Shp2 Tyrosine Phosphatase in Thymocytes Suppresses Both Pre-TCR and TCR Signals J. Immunol., November 1, 2006; 177(9): 5990 - 5996. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Carter, G. M. Calabrese, M. Naganuma, and U. Lorenz Deficiency of the Src Homology Region 2 Domain-Containing Phosphatase 1 (SHP-1) Causes Enrichment of CD4+CD25+ Regulatory T Cells J. Immunol., June 1, 2005; 174(11): 6627 - 6638. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. C. J. Fawcett and U. Lorenz Localization of Src Homology 2 Domain-Containing Phosphatase 1 (SHP-1) to Lipid Rafts in T Lymphocytes: Functional Implications and a Role for the SHP-1 Carboxyl Terminus J. Immunol., March 1, 2005; 174(5): 2849 - 2859. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Puthier, F. Joly, M. Irla, M. Saade, G. Victorero, B. Loriod, and C. Nguyen A General Survey of Thymocyte Differentiation by Transcriptional Analysis of Knockout Mouse Models J. Immunol., November 15, 2004; 173(10): 6109 - 6118. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. G. Sathish, J. Walters, J. C. Luo, K. G. Johnson, F. G. LeRoy, P. Brennan, K. P. Kim, S. P. Gygi, B. G. Neel, and R. J. Matthews CD22 Is a Functional Ligand for SH2 Domain-containing Protein-tyrosine Phosphatase-1 in Primary T Cells J. Biol. Chem., November 12, 2004; 279(46): 47783 - 47791. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. E. Kilgore, J. D. Carter, U. Lorenz, and B. D. Evavold Cutting Edge: Dependence of TCR Antagonism on Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase Activity J. Immunol., May 15, 2003; 170(10): 4891 - 4895. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Deng, A. Minguela, R. Z. Hussain, A. E. Lovett-Racke, C. Radu, E. S. Ward, and M. K. Racke Expression of the Tyrosine Phosphatase Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase 1 Determines T Cell Activation Threshold and Severity of Experimental Autoimmune Encephalomyelitis J. Immunol., May 1, 2002; 168(9): 4511 - 4518. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. K. Pathak and T. Yi Sodium Stibogluconate Is a Potent Inhibitor of Protein Tyrosine Phosphatases and Augments Cytokine Responses in Hemopoietic Cell Lines J. Immunol., September 15, 2001; 167(6): 3391 - 3397. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. G. Sathish, K. G. Johnson, K. J. Fuller, F. G. LeRoy, L. Meyaard, M. J. Sims, and R. J. Matthews Constitutive Association of SHP-1 with Leukocyte-Associated Ig-Like Receptor-1 in Human T Cells J. Immunol., February 1, 2001; 166(3): 1763 - 1770. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Ohteki, M. Parsons, A. Zakarian, R. G. Jones, L. T. Nguyen, J. R. Woodgett, and P. S. Ohashi Negative Regulation of T Cell Proliferation and Interleukin 2 Production by the Serine Threonine Kinase Gsk-3 J. Exp. Med., July 3, 2000; 192(1): 99 - 104. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. G. Chiang and B. M. Sefton Specific Dephosphorylation of the Lck Tyrosine Protein Kinase at Tyr-394 by the SHP-1 Protein-tyrosine Phosphatase J. Biol. Chem., June 15, 2001; 276(25): 23173 - 23178. [Abstract] [Full Text] [PDF]
|
|