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.
A partial human LCK defect causes a T cell immunodeficiency with intestinal inflammation / Lui, Victor G.; Hoenig, Manfred; Cabrera-Martinez, Berenice; Baxter, Ryan M.; Garcia-Perez, Josselyn E.; Bailey, Olivia; Acharya, Atanu; Lundquist, Karl; Capera, Jesusa; Matusewicz, Paul; Hartl, Frederike A.; D’Abramo, Marco; Alba, Josephine; Jacobsen, Eva-Maria; Niewolik, Doris; Lorenz, Myriam; Pannicke, Ulrich; Schulz, Ansgar S.; Debatin, Klaus-Michael; Schamel, Wolfgang W.; Minguet, Susana; Gumbart, James C.; Dustin, Michael L.; Cambier, John C.; Schwarz, Klaus; Hsieh, Elena W. Y.. - In: JOURNAL OF EXPERIMENTAL MEDICINE. - ISSN 0022-1007. - 221:1(2024). [10.1084/jem.20230927]
A partial human LCK defect causes a T cell immunodeficiency with intestinal inflammation
D’Abramo, Marco;Alba, Josephine;
2024
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
