Involvement of the SHP-1 tyrosine phosphatase in regulation of T cell selection

Jinyi Zhang, Ally Khan Somani, Darren Yuen, Ye Yang, Paul E. Love, Katherine A. Siminovitch

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

The selection events shaping T cell development in the thymus represent the outcome of TCR-driven intracellular signaling cascades evoked by Ag receptor interaction with cognate ligand. In view of data indicating TCR- evoked thymocyte proliferation to be negatively modulated by the SHP-1 tyrosine phosphatase, a potential role for SHP-1 in regulating selection processes was investigated by analysis of T cell development in H-Y TCR transgenic mice rendered SHP-1 deficient by introduction of the viable motheaten mutation or a dominant negative SHP-1-encoding transgene. Characterization of thymocyte and peripheral T cell populations in H-Y TCR- viable motheaten mice revealed TCR-evoked proliferation as well as the positive and negative selection of H-Y-specific thymocytes to be enhanced in these mice, thus implicating SHP-1 in the negative regulation of each of these processes. T cell selection processes were also augmented in H-Y TCR mice carrying a transgene driving lymphoid-restricted expression of a catalytically inert, dominant-negative form of SHP-1. SHP-1-negative effects on thymocyte TCR signaling were not influenced by co-cross-linking of the CD28 costimulatory and/or CTLA-4 inhibitory receptors and appear, accordingly, to be realized independently of these comodulators. These observations indicate that SHP-1 raises the signaling threshold required for both positive and negative selection and reveal the inhibitory effects of SHP-1 on TCR signaling to be cell autonomous. The demonstrated capacity for SHP-1 to inhibit TCR-evoked proliferation and selection indicate SHP-1 modulatory effects on the magnitude of TCR-generated signal to be a key factor in determining the cellular consequences of TCR-ligand interaction.

Original languageEnglish (US)
Pages (from-to)3012-3021
Number of pages10
JournalJournal of Immunology
Volume163
Issue number6
StatePublished - Sep 15 1999
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Zhang, J., Somani, A. K., Yuen, D., Yang, Y., Love, P. E., & Siminovitch, K. A. (1999). Involvement of the SHP-1 tyrosine phosphatase in regulation of T cell selection. Journal of Immunology, 163(6), 3012-3021.