Primary T-cell immunodeficiency with immunodysregulation caused by autosomal recessive LCK deficiency

J Allergy Clin Immunol. 2012 Nov;130(5):1144-1152.e11. doi: 10.1016/j.jaci.2012.07.029. Epub 2012 Sep 15.


Background: Signals emanating from the antigen T-cell receptor (TCR) are required for T-cell development and function. The T lymphocyte-specific protein tyrosine kinase (Lck) is a key component of the TCR signaling machinery. On the basis of its function, we considered LCK a candidate gene in patients with combined immunodeficiency.

Objective: We identify and describe a child with a T-cell immunodeficiency caused by a homozygous missense mutation of the LCK gene (c.1022T>C) resulting from uniparental disomy.

Methods: Genetic, molecular, and functional analyses were performed to characterize the Lck deficiency, and the associated clinical and immunologic phenotypes are reported.

Results: The mutant LCK protein (p.L341P) was weakly expressed with no kinase activity and failed to reconstitute TCR signaling in LCK-deficient T cells. The patient presented with recurrent respiratory tract infections together with predominant early-onset inflammatory and autoimmune manifestations. The patient displayed CD4(+) T-cell lymphopenia and low levels of CD4 and CD8 expression on the T-cell surface. The residual T lymphocytes had an oligoclonal T-cell repertoire and exhibited a profound TCR signaling defect, with only weak tyrosine phosphorylation signals and no Ca(2+) mobilization in response to TCR stimulation.

Conclusion: We report a new form of T-cell immunodeficiency caused by a LCK gene defect, highlighting the essential role of Lck in human T-cell development and responses. Our results also point out that defects in the TCR signaling cascade often result in abnormal T-cell differentiation and functions, leading to an important risk factor for inflammation and autoimmunity.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4-Positive T-Lymphocytes / immunology*
  • Calcium Signaling / genetics
  • Cells, Cultured
  • Child, Preschool
  • DNA Mutational Analysis
  • Female
  • France
  • Genes, Recessive / genetics
  • Genetic Predisposition to Disease
  • Humans
  • Immunologic Deficiency Syndromes / diagnosis*
  • Immunologic Deficiency Syndromes / genetics*
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / chemistry
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / genetics*
  • Mutation, Missense / genetics
  • Pedigree
  • Polymorphism, Genetic
  • Primary Immunodeficiency Diseases
  • Receptors, Antigen, T-Cell / metabolism
  • T-Lymphocytopenia, Idiopathic CD4-Positive / diagnosis*
  • T-Lymphocytopenia, Idiopathic CD4-Positive / genetics*


  • Receptors, Antigen, T-Cell
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)

Supplementary concepts

  • T cell immunodeficiency primary