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

M. E. Elder, S. Skoda-Smith, T. A. Kadlecek, F. Wang, J. Wu, A. Weiss

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)656-661
Number of pages6
JournalJournal of Immunology
Volume166
Issue number1
DOIs
StatePublished - Jan 1 2001

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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