A partial human LCK defect causes a T cell immunodeficiency with intestinal inflammation-Reference-Cited by-同舟云学术

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

Published:2023-11-14 Issue:1 Volume:221 Page:
ISSN:0022-1007
Container-title:Journal of Experimental Medicine
language:en
Short-container-title:

Author:

Lui Victor G.¹^ORCID,Hoenig Manfred²^ORCID,Cabrera-Martinez Berenice¹^ORCID,Baxter Ryan M.¹^ORCID,Garcia-Perez Josselyn E.¹^ORCID,Bailey Olivia¹^ORCID,Acharya Atanu³⁴^ORCID,Lundquist Karl³^ORCID,Capera Jesusa⁵^ORCID,Matusewicz Paul⁶⁷⁸^ORCID,Hartl Frederike A.⁶⁷⁸^ORCID,D’Abramo Marco⁹^ORCID,Alba Josephine¹⁰^ORCID,Jacobsen Eva-Maria²^ORCID,Niewolik Doris¹¹^ORCID,Lorenz Myriam¹¹^ORCID,Pannicke Ulrich¹¹^ORCID,Schulz Ansgar S.²^ORCID,Debatin Klaus-Michael²^ORCID,Schamel Wolfgang W.⁶⁷⁸^ORCID,Minguet Susana⁶⁷⁸^ORCID,Gumbart James C.³^ORCID,Dustin Michael L.⁵^ORCID,Cambier John C.¹¹²^ORCID,Schwarz Klaus¹¹¹³^ORCID,Hsieh Elena W.Y.¹¹²¹⁴^ORCID

Affiliation:

1. School of Medicine, University of Colorado Anschutz Medical Campus 1 Department of Immunology and Microbiology, , Aurora, CO, USA

2. University Medical Center Ulm 2 Department of Pediatrics, , Ulm, Germany

3. School of Physics, Georgia Institute of Technology 3 , Atlanta, GA, USA

4. Syracuse University 4 BioInspired Syracuse and Department of Chemistry, , Syracuse, NY, USA

5. The Kennedy Institute of Rheumatology, University of Oxford 5 Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, , Oxford, UK

6. Faculty of Biology, University of Freiburg 6 , Freiburg, Germany

7. BIOSS Centre for Biological Signalling Studies and CIBSS Centre for Integrative Biological Signalling Studies, University of Freiburg 7 , Freiburg, Germany

8. Center of Chronic Immunodeficiency, University Clinics and Medical Faculty, University 8 , Freiburg, Germany

9. Sapienza University of Rome 9 Department of Chemistry, , Rome, Italy

10. Université de Fribourg 10 Department of Biology, , Fribourg, Switzerland

11. Institute for Transfusion Medicine, University of Ulm 11 , Ulm, Germany

12. Human Immunology and Immunotherapy Initiative, University of Colorado Anschutz School of Medicine 12 , Aurora, CO, USA

13. Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Wuerttemberg-Hessen 13 , Ulm, Germany

14. Children’s Hospital Colorado, University of Colorado Anschutz School of Medicine 14 Department of Pediatrics, Section of Allergy and Immunology, , Aurora, CO, USA

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.

Funder

Immunology Training Program

National Science Foundation

Jeffrey Modell Foundation

National Institute of Arthritis and Musculoskeletal and Skin Diseases

Cancer Research Institute

Kennedy Trust

Wellcome Trust

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy