A 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 (Lck(P440S/P440S)) loss-of-function LCK causes disease with differing phenotypes. While both Lck(−/−) and Lck(P440S/P440S) mice exhibit arrested thymic T cell development and profound T cell lymphopenia, only Lck(P440S/P440S) mice show residual T cell proliferation, cytokine production, and intestinal inflammation. Furthermore, the intestinal disease in the Lck(P440S/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.