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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.
Afiliación
  • Lui VG; Department of Immunology and Microbiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Hoenig M; Department of Pediatrics, University Medical Center Ulm, Ulm, Germany.
  • Cabrera-Martinez B; Department of Immunology and Microbiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Baxter RM; Department of Immunology and Microbiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Garcia-Perez JE; Department of Immunology and Microbiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Bailey O; Department of Immunology and Microbiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Acharya A; School of Physics, Georgia Institute of Technology , Atlanta, GA, USA.
  • Lundquist K; BioInspired Syracuse and Department of Chemistry, Syracuse University, Syracuse, NY, USA.
  • Capera J; School of Physics, Georgia Institute of Technology , Atlanta, GA, USA.
  • Matusewicz P; Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
  • Hartl FA; Faculty of Biology, University of Freiburg , Freiburg, Germany.
  • D'Abramo M; BIOSS Centre for Biological Signalling Studies and CIBSS Centre for Integrative Biological Signalling Studies, University of Freiburg , Freiburg, Germany.
  • Alba J; Center of Chronic Immunodeficiency, University Clinics and Medical Faculty, University , Freiburg, Germany.
  • Jacobsen EM; Faculty of Biology, University of Freiburg , Freiburg, Germany.
  • Niewolik D; BIOSS Centre for Biological Signalling Studies and CIBSS Centre for Integrative Biological Signalling Studies, University of Freiburg , Freiburg, Germany.
  • Lorenz M; Center of Chronic Immunodeficiency, University Clinics and Medical Faculty, University , Freiburg, Germany.
  • Pannicke U; Department of Chemistry, Sapienza University of Rome, Rome, Italy.
  • Schulz AS; Department of Biology, Université de Fribourg, Fribourg, Switzerland.
  • Debatin KM; Department of Pediatrics, University Medical Center Ulm, Ulm, Germany.
  • Schamel WW; Institute for Transfusion Medicine, University of Ulm , Ulm, Germany.
  • Minguet S; Institute for Transfusion Medicine, University of Ulm , Ulm, Germany.
  • Gumbart JC; Institute for Transfusion Medicine, University of Ulm , Ulm, Germany.
  • Dustin ML; Department of Pediatrics, University Medical Center Ulm, Ulm, Germany.
  • Cambier JC; Department of Pediatrics, University Medical Center Ulm, Ulm, Germany.
  • Schwarz K; Faculty of Biology, University of Freiburg , Freiburg, Germany.
  • Hsieh EWY; BIOSS Centre for Biological Signalling Studies and CIBSS Centre for Integrative Biological Signalling Studies, University of Freiburg , Freiburg, Germany.
J Exp Med ; 221(1)2024 Jan 01.
Article en En | MEDLINE | ID: mdl-37962568
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 (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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Síndromes de Inmunodeficiencia / Linfopenia Límite: Animals / Humans / Infant Idioma: En Revista: J Exp Med Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Síndromes de Inmunodeficiencia / Linfopenia Límite: Animals / Humans / Infant Idioma: En Revista: J Exp Med Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos