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.
Fabian Hauck  1 ,  Clotilde Randriamampita ,  Emmanuel Martin ,  Stéphane Gerart ,  Nathalie Lambert ,  Annick Lim ,  Jean Soulier ,  Zosia Maciorowski ,  Fabien Touzot ,  Despina Moshous ,  Pierre Quartier ,  Sébastien Heritier ,  Stéphane Blanche ,  Fréderic Rieux-Laucat ,  Nicole Brousse ,  Isabelle Callebaut ,  André Veillette ,  Claire Hivroz ,  Alain Fischer ,  Sylvain Latour ,  Capucine Picard
Affiliations
  • 1. INSERM 768, Laboratoire du Développement Normal et Pathologique du Système Immunitaire, Hôpital Necker-Enfants Malades, Paris, France.
PMID: 22985903 DOI: 10.1016/j.jaci.2012.07.029
Abstract

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.