Distinct T cell developmental consequences in humans and mice expressing identical mutations in the DLAARN motif of ZAP-70

J Immunol. 2001 Jan 1;166(1):656-61. doi: 10.4049/jimmunol.166.1.656.

Abstract

The protein tyrosine kinase, ZAP-70, is pivotally involved in transduction of Ag-binding signals from the TCR required for T cell activation and development. Defects in ZAP-70 result in SCID in humans and mice. We describe an infant with SCID due to a novel ZAP-70 mutation, comparable with that which arose spontaneously in an inbred mouse colony. The patient inherited a homozygous missense mutation within the highly conserved DLAARN motif in the ZAP-70 kinase domain. Although the mutation only modestly affected protein stability, catalytic function was absent. Despite identical changes in the amino acid sequence of ZAP-70, the peripheral T cell phenotypes of our patient and affected mice are distinct. ZAP-70 deficiency in this patient, as in other humans, is characterized by abundant nonfunctional CD4(+) T cells and absent CD8(+) T cells. In contrast, ZAP-70-deficient mice lack both major T cell subsets. Although levels of the ZAP-70-related protein tyrosine kinase, Syk, may be sufficiently increased in human thymocytes to rescue CD4 development, survival of ZAP-70-deficient T cells in the periphery does not appear to be dependent on persistent up-regulation of Syk expression.

Publication types

  • Case Reports
  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Motifs / genetics
  • Amino Acid Motifs / immunology
  • Animals
  • Arginine / genetics
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / pathology
  • Catalysis
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Cell Survival / genetics
  • Cell Survival / immunology
  • Cells, Cultured
  • Cysteine / genetics
  • Enzyme Activation / genetics
  • Enzyme Activation / immunology
  • Enzyme Precursors / biosynthesis
  • Humans
  • Infant
  • Intracellular Signaling Peptides and Proteins
  • Lymphocyte Activation / genetics
  • Male
  • Mice
  • Mutation, Missense*
  • Phosphorylation
  • Phosphotyrosine / metabolism
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / biosynthesis
  • Protein-Tyrosine Kinases / deficiency
  • Protein-Tyrosine Kinases / genetics*
  • Protein-Tyrosine Kinases / metabolism
  • Receptors, Antigen, T-Cell / physiology
  • Severe Combined Immunodeficiency / genetics
  • Severe Combined Immunodeficiency / immunology
  • Severe Combined Immunodeficiency / pathology
  • Syk Kinase
  • T-Lymphocyte Subsets / enzymology*
  • T-Lymphocyte Subsets / pathology*
  • Up-Regulation / genetics
  • Up-Regulation / immunology
  • ZAP-70 Protein-Tyrosine Kinase

Substances

  • Enzyme Precursors
  • Intracellular Signaling Peptides and Proteins
  • Receptors, Antigen, T-Cell
  • Phosphotyrosine
  • Arginine
  • Protein-Tyrosine Kinases
  • SYK protein, human
  • Syk Kinase
  • Syk protein, mouse
  • ZAP-70 Protein-Tyrosine Kinase
  • ZAP70 protein, human
  • Zap70 protein, mouse
  • Cysteine