Primary T-cell immunodeficiency with immunodysregulation caused by autosomal recessive LCK deficiency - 31/10/12

Doi : 10.1016/j.jaci.2012.07.029

Fabian Hauck, MD ^a,^b, Clotilde Randriamampita, PhD ^c, Emmanuel Martin, PhD ^a, Stéphane Gerart, PhD ^a, Nathalie Lambert, AS ^d, Annick Lim, MS ^e, Jean Soulier, MD, PhD ^f, Zosia Maciorowski, BS ^g, Fabien Touzot, MD, PhD ^h, Despina Moshous, MD, PhD ^h, Pierre Quartier, MD ^b,^h, Sébastien Heritier, MD ^b,^h, Stéphane Blanche, MD ^b,^h, Fréderic Rieux-Laucat, PhD ^a, Nicole Brousse, MD ^b,ⁱ, Isabelle Callebaut, PhD ^j, André Veillette, MD ^k, Claire Hivroz, PhD ^l, Alain Fischer, MD, PhD ^a,^b,^h, Sylvain Latour, PhD ^a,^⁎^{^{These authors contributed equally to this work.}} , Capucine Picard, MD, PhD ^b,^d,^m,^{^{These authors contributed equally to this work.}}
^a INSERM 768, Laboratoire du Développement Normal et Pathologique du Système Immunitaire, Hôpital Necker-Enfants Malades, Paris, France
^b Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France
^c INSERM 567-CNRS UMR 8104, Institut Cochin, Paris, France
^d Centre d’Etude des Déficits Immunitaires, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
^e Unité de Régulation Immunitaire et Vaccinologie, Institut Pasteur Paris, Paris, France
^f INSERM 944-CNRS UMR 7212, Hôpital Saint-Louis, AP-HP, Paris, France
^g Flow Cytometry Core Facility, Institut Curie, Paris, France
^h Unité d’Immunologie et Hématologie Pédiatrique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
ⁱ Service d’Anatomie et de Cytologie Pathologiques, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
^j Institut de Minéralogie et de Physique des Milieux Condensés, CNRS UMR 7590, Universités Pierre et Marie Curie et Paris Diderot, Paris, France
^k Molecular Oncology Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, Québec, Canada
^l INSERM 932, Institut Curie, Paris, France
^m INSERM 980, Laboratory of Human Genetics of Infectious Disease, Necker Enfants Malades Branch, Paris, France

Corresponding author: Sylvain Latour, PhD, INSERM 768, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, Paris 75015, France.

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 Ca²⁺ 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.

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Key words : CD4, lymphopenia, autoinflammation, recurrent infections, LCK, SRC tyrosine kinase, genetic defect, immunodeficiency, T-cell receptor signaling

Abbreviations used : CDR3, CD62L, CID, ERK, FITC, FOXP3, GFP, ITAM, MAPK, NK, PE, PLC, PMA, TCR, TRA/B/G/DV, TRA/B/G/DC, Treg, UPD, WT, ZAP-70

Plan

Methods

Results

Clinical features

Immunologic phenotype

Lck deficiency

Defective early TCR signaling in p.L341P Lck–expressing cells

Discussion

Supported by grants from INSERM, Agence Nationale de la Recherche (ANR-08-MIEN-012-01, France), and the European Research Council (ERC-2009-AdG_20090506 no. FP7-249816). S.L. is a senior scientist at the Centre National de la Recherche Scientifique (France) and F.H. is a clinician at the University Children’s Hospital of Dresden (Germany) and holds fellowships from the German Research Council/DFG (HA 5967/1-1) and the Fondation IMAGINE (France). S.G. holds a fellowship from the Ministère de la Recherche and l’Ecole Polytechnique (France) and the Fondation ARC pour la Recherche sur le Cancer (ARC) (France). E.M. is supported by the ANR (France). D.M. received a Robert A. Good/Jeffrey Modell fellowship.

Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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Vol 130 - N° 5

P. 1144 - novembre 2012 Retour au numéro

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Primary T-cell immunodeficiency with immunodysregulation caused by autosomal recessive LCK deficiency - 31/10/12

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