Involvement of p21ras distinguishes positive and negative selection in thymocytes

EMBO J. 1995 Jan 16;14(2):276-85.

Abstract

Small molecular weight GTP binding proteins of the ras family have been implicated in signal transduction from the T cell antigen receptor (TCR). To test the importance of p21ras in the control of thymocyte development, we generated mice expressing a dominant-negative p21ras protein (H-rasN17) in T lineage cells under the control of the lck proximal promoter. Proliferation of thymocytes from lck-H-rasN17 mice in response to TCR stimulation was nearly completely blocked, confirming the importance of p21ras in mediating TCR-derived signals in mature CD4+8- or CD8+4- thymocytes. In contrast, some TCR-derived signals proceeded unimpaired in the CD4+8+ thymocytes of mice expressing dominant-negative p21ras. Analysis of thymocyte development in mice made doubly transgenic for the H-Y-specific TCR and lck-H-rasN17 demonstrated that antigen-specific negative selection occurs normally in the presence of p21H-rasN17. Superantigen-induced negative selection in vivo also proceeded unhindered in H-rasN17 thymocytes. In contrast, positive selection of thymocytes in the H-Y mice was severely compromised by the presence of p21H-rasN17. These observations demonstrate that positive and negative selection, two conceptually antithetical consequences of TCR stimulation, are biochemically distinguishable.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Differentiation
  • Lymphocyte Activation
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Oncogene Protein p21(ras) / genetics
  • Oncogene Protein p21(ras) / physiology*
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-fyn
  • Receptors, Antigen, T-Cell / physiology
  • Signal Transduction
  • T-Lymphocytes / metabolism
  • Thymus Gland / cytology*
  • Thymus Gland / metabolism

Substances

  • Proto-Oncogene Proteins
  • Receptors, Antigen, T-Cell
  • Protein-Tyrosine Kinases
  • Fyn protein, mouse
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • Proto-Oncogene Proteins c-fyn
  • Oncogene Protein p21(ras)