A partial human LCK defect causes a T cell immunodeficiency with intestinal inflammation.
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
01 Jan 2024
01 Jan 2024
Historique:
received:
29
05
2023
revised:
09
09
2023
accepted:
27
10
2023
medline:
15
11
2023
pubmed:
14
11
2023
entrez:
14
11
2023
Statut:
ppublish
Résumé
Lymphocyte-specific protein tyrosine kinase (LCK) is essential for T cell antigen receptor (TCR)-mediated signal transduction. Here, we report two siblings homozygous for a novel LCK variant (c.1318C>T; P440S) characterized by T cell lymphopenia with skewed memory phenotype, infant-onset recurrent infections, failure to thrive, and protracted diarrhea. The patients' T cells show residual TCR signal transduction and proliferation following anti-CD3/CD28 and phytohemagglutinin (PHA) stimulation. We demonstrate in mouse models that complete (Lck-/-) versus partial (LckP440S/P440S) loss-of-function LCK causes disease with differing phenotypes. While both Lck-/- and LckP440S/P440S mice exhibit arrested thymic T cell development and profound T cell lymphopenia, only LckP440S/P440S mice show residual T cell proliferation, cytokine production, and intestinal inflammation. Furthermore, the intestinal disease in the LckP440S/P440S mice is prevented by CD4+ T cell depletion or regulatory T cell transfer. These findings demonstrate that P440S LCK spares sufficient T cell function to allow the maturation of some conventional T cells but not regulatory T cells-leading to intestinal inflammation.
Identifiants
pubmed: 37962568
pii: 276408
doi: 10.1084/jem.20230927
pmc: PMC10644909
pii:
doi:
Substances chimiques
CD28 Antigens
0
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
EC 2.7.10.2
Receptors, Antigen, T-Cell
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIAID NIH HHS
ID : T32 AI007405
Pays : United States
Organisme : NIAMS NIH HHS
ID : K23AR070897
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA046934
Pays : United States
Organisme : NIAMS NIH HHS
ID : K23 AR070897
Pays : United States
Organisme : Wellcome Trust
ID : 100262Z/12/Z
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Cancer Research Institute
ID : CRI4503
Pays : United States
Informations de copyright
© 2023 Lui et al.
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