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
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