Essential role for ZAP-70 in both positive and negative selection of thymocytes

Nature. 1995 Aug 3;376(6539):435-8. doi: 10.1038/376435a0.


During thymic development, T cells that can recognize foreign antigen in association with self major histocompatibility complex (MHC) are selected for survival (positive selection) and autoreactive T cells are eliminated (negative selection). Both of these selective events are mediated by interaction between the T-cell receptor (TCR) and the peptide-MHC complex. But the signalling pathways that lead to cell survival or to cell death are still unclear. ZAP-70 is a protein tyrosine kinase (PTK) that is associated with the TCR signalling subunits (CD3 and zeta) and is expressed in T cells and natural killer cells. It has been shown that ZAP-70 plays a crucial role in T-cell activation and development. Here we show that mice lacking ZAP-70 had neither CD4 nor CD8 single-positive T cells, but human ZAP-70 reconstituted both CD4 and CD8 single-positive populations. Moreover, ZAP-70-/- thymocytes were not deleted by peptide antigens. Natural killer cell function was intact in the absence of ZAP-70. These data suggest that ZAP-70 is a central signalling molecule during thymic selection for CD4 and CD8 lineage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / cytology*
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / cytology*
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Differentiation / physiology
  • Cell Line
  • Cells, Cultured
  • Female
  • Gene Deletion
  • Humans
  • Killer Cells, Natural / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / physiology*
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / physiology*
  • Severe Combined Immunodeficiency / immunology
  • Spleen / cytology
  • Spleen / immunology
  • Thymus Gland / cytology*
  • Thymus Gland / immunology
  • Tumor Cells, Cultured
  • ZAP-70 Protein-Tyrosine Kinase


  • Receptors, Antigen, T-Cell
  • Protein-Tyrosine Kinases
  • ZAP-70 Protein-Tyrosine Kinase
  • ZAP70 protein, human
  • Zap70 protein, mouse