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.