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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.

Original publication

DOI

10.1084/jem.20230927

Type

Journal article

Journal

The Journal of experimental medicine

Publication Date

01/2024

Volume

221

Addresses

Department of Immunology and Microbiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Keywords

CD4-Positive T-Lymphocytes, Animals, Humans, Mice, Lymphopenia, Immunologic Deficiency Syndromes, Inflammation, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Receptors, Antigen, T-Cell, Infant, CD28 Antigens