A partial human LCK defect causes a T cell immunodeficiency with intestinal inflammation

Victor G. Lui, Manfred Hoenig, Berenice Cabrera-Martinez, Ryan M. Baxter, Josselyn E. Garcia-Perez, Olivia Bailey, Atanu Acharya, Karl Lundquist, Jesusa Capera, Paul Matusewicz, Frederike A. Hartl, Marco D’abramo, Josephine Alba, Eva Maria Jacobsen, Doris Niewolik, Myriam Lorenz, Ulrich Pannicke, Ansgar S. Schulz, Klaus Michael Debatin, Wolfgang W. SchamelSusana Minguet, James C. Gumbart, Michael L. Dustin, John C. Cambier, Klaus Schwarz, Elena W.Y. Hsieh

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


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 languageEnglish (US)
Article numbere20230927
JournalJournal of Experimental Medicine
Issue number1
StatePublished - 2024

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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