biostudies-literatureLui VGNational Institute of Arthritis and Musculoskeletal and Skin DiseasesNIDDK NIH HHSImmunology Training ProgramNIAID NIH HHSNCI NIH HHSJeffrey Modell FoundationKennedy TrustNIAMS NIH HHSWellcome TrustCancer Research InstituteNational Science Foundatione20230927https://www.ebi.ac.uk/biostudies/studies/S-EPMC10644909biostudies-literatureUnknown221(1)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 resiThe Journal of experimental medicineA partial human LCK defect causes a T cell immunodeficiency with intestinal inflammation.PMC10644909P30 CA046934P30 DK116073CRI4503100262Z/12/ZK23 AR070897K23AR070897KENN202117DGE-1938058224343/Z/21/ZT32 AI07405T32 AI007405KENN202114Acharya AJacobsen EMCapera JMinguet SLundquist KDustin MLBaxter RMCambier JCGumbart JCPannicke UHoenig MSchwarz KLui VGCabrera-Martinez BHartl FAGarcia-Perez JEMatusewicz PNiewolik DSchamel WWD'Abramo MDebatin KMLorenz MSchulz ASBailey OAlba JHsieh EWYfalseA partial human LCK defect causes a T cell immunodeficiency with intestinal inflammation.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 resi2024-01-01T00:00:00Z2024 Jan2026-07-14T18:38:30.722Z2024-11-09T11:16:28.796ZS-EPMC106449093796256810.1084/jem.20230927