INSERM 768, Laboratoire du Développement Normal et Pathologique du Système Immunitaire, Hôpital Necker-Enfants Malades, Paris, France.
J Allergy Clin Immunol. 2012 Nov;130(5):1144-1152.e11. doi: 10.1016/j.jaci.2012.07.029. Epub 2012 Sep 15.
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.
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.
Genetic, molecular, and functional analyses were performed to characterize the Lck deficiency, and the associated clinical and immunologic phenotypes are reported.
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.
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.
抗原 T 细胞受体（TCR）发出的信号对于 T 细胞的发育和功能是必需的。T 淋巴细胞特异性蛋白酪氨酸激酶（Lck）是 TCR 信号机制的关键组成部分。基于其功能，我们认为 LCK 是联合免疫缺陷患者的候选基因。
我们发现并描述了一名 T 细胞免疫缺陷患儿，其 LCK 基因（c.1022T>C）发生纯合错义突变，导致单亲二体。
进行了遗传、分子和功能分析，以表征 Lck 缺陷，并报告相关的临床和免疫表型。
突变的 LCK 蛋白（p.L341P）表达较弱，没有激酶活性，并且不能在 LCK 缺陷的 T 细胞中重建 TCR 信号。该患者表现为反复呼吸道感染，伴有早期炎症和自身免疫表现为主。患者表现为 CD4(+)T 细胞淋巴细胞减少，T 细胞表面 CD4 和 CD8 表达水平降低。残留的 T 淋巴细胞具有寡克隆 T 细胞库，表现出明显的 TCR 信号缺陷，仅存在微弱的酪氨酸磷酸化信号，并且对 TCR 刺激没有 Ca(2+)动员。
我们报告了一种由 LCK 基因突变引起的新型 T 细胞免疫缺陷，强调了 Lck 在人类 T 细胞发育和反应中的重要作用。我们的结果还指出，TCR 信号级联中的缺陷通常导致异常的 T 细胞分化和功能，从而成为炎症和自身免疫的一个重要危险因素。
