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

Published: 20 October 2023| Version 2 | DOI: 10.17632/n8658z8fg5.2
Victor Lui, Elena Hsieh


Partial T cell primary immunodeficiency disorders (PIDD) are a group of genetic disorders that have partial reduction of T cell number/function, and are commonly associated with autoimmune and inflammatory complications. T cell receptor (TCR) signaling is initiated by Lymphocyte cell-specific protein-tyrosine kinase (LCK). A novel homozygous mutation in LCK (p.Pro440Ser, LCK P440S) was identified in two siblings who were born to consanguineous parents, presenting with T lymphopenia, recurrent viral and fungal infections, and gastrointestinal inflammatory complications. We hypothesize the P440S mutation impairs LCK expression/function such that T cell-mediated intestinal immunity is dysfunctional, leading to inflammatory bowel disease (IBD). We generated a cell line and a mouse model that harbor the mutant kinase, and then performed downstream immunophenotypic and functional assessments. The P440S mutation results in shorter protein half-life, decreased protein expression, and defective TCR signaling responses. The P440S mouse demonstrates impaired thymocyte development with T cell lymphopenia, skewed memory phenotype of peripheral T cells, and colitis. The Lck knock out mouse replicates the T cell aberrations in the P440S mouse, but do not develop colitis, suggesting that the partial loss of Lck function drives colitis development. Our findings explain the aberrant immunological presentation of the human P440S patients, advance our understanding of IBD in the context of T cell PIDD, and establish a model system with which to develop therapies against IBD. Within this repository are .fcs files from flow cytometry and mass cytometry experiments that were collected for the publication of this project. They include data collected for the phenotyping of a novel P440S Lck mouse model, functional assessment of P440S T cells, and determination of the effects of CD4 depletion and Treg infusion into these mice.


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Flow cytometry data were collected either on a LSR Fortessa or Cytek Aurora flow cytometer. Data were analyzed using FloJo or Cell Engine.


University of Colorado Denver - Anschutz Medical Campus


Immunology, Cell Signaling, Colitis