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Distinct T cell developmental consequences in humans and mice expressing identical mutations in the DLAARN motif of
M E Elder1, S Skoda-Smith, T A Kadlecek
1Department of Pediatrics, University of California, San Francisco, CA 94143, USA. elderm@peds.ucsf.edu
Insights
A novel ZAP-70 mutation causes severe combined immunodeficiency (SCID). This ZAP-70 defect leads to distinct T cell phenotypes in affected humans versus mice.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- ZAP-70 (zeta-chain-associated protein kinase 70) is crucial for T cell receptor (TCR) signaling, essential for T cell activation and development.
- Defects in ZAP-70 lead to severe combined immunodeficiency (SCID), a primary immunodeficiency disease, observed in both humans and mice.
Observation:
- A novel homozygous missense mutation in the conserved DLAARN motif of the ZAP-70 kinase domain was identified in an infant with SCID.
- This mutation significantly impaired ZAP-70 catalytic function while only modestly affecting protein stability.
Findings:
- The patient exhibited abundant nonfunctional CD4+ T cells and absent CD8+ T cells, a distinct peripheral T cell phenotype compared to ZAP-70-deficient mice, which lack both T cell subsets.
- While Syk (spleen tyrosine kinase) upregulation may rescue CD4+ T cell development in humans, peripheral T cell survival in ZAP-70 deficiency is not dependent on sustained Syk expression.
Implications:
- This study highlights distinct species-specific T cell responses to ZAP-70 deficiency, offering insights into T cell development and survival mechanisms.
- Understanding these differences can inform therapeutic strategies for SCID and other T cell-related disorders.
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.
