Combined Immunodeficiency Caused by a Novel Nonsense Mutation in LCK

Baerbel Keller, Shlomit Kfir-Erenfeld, Paul Matusewicz, Frederike Hartl, Atar Lev, Yu Nee Lee, Amos J. Simon, Tali Stauber, Orly Elpeleg, Raz Somech, Polina Stepensky, Susana Minguet, Burkhart Schraven, Klaus Warnatz

Research output: Contribution to journalArticlepeer-review


Abstract: Mutations affecting T-cell receptor (TCR) signaling typically cause combined immunodeficiency (CID) due to varying degrees of disturbed T-cell homeostasis and differentiation. Here, we describe two cousins with CID due to a novel nonsense mutation in LCK and investigate the effect of this novel nonsense mutation on TCR signaling, T-cell function, and differentiation. Patients underwent clinical, genetic, and immunological investigations. The effect was addressed in primary cells and LCK-deficient T-cell lines after expression of mutated LCK. Results: Both patients primarily presented with infections in early infancy. The LCK mutation led to reduced expression of a truncated LCK protein lacking a substantial part of the kinase domain and two critical regulatory tyrosine residues. T cells were oligoclonal, and especially naïve CD4 and CD8 T-cell counts were reduced, but regulatory and memory including circulating follicular helper T cells were less severely affected. A diagnostic hallmark of this immunodeficiency is the reduced surface expression of CD4. Despite severely impaired TCR signaling mTOR activation was partially preserved in patients’ T cells. LCK-deficient T-cell lines reconstituted with mutant LCK corroborated partially preserved signaling. Despite detectable differentiation of memory and effector T cells, their function was severely disturbed. NK cell cytotoxicity was unaffected. Residual TCR signaling in LCK deficiency allows for reduced, but detectable T-cell differentiation, while T-cell function is severely disturbed. Our findings expand the previous report on one single patient on the central role of LCK in human T-cell development and function. Graphical Abstract: [Figure not available: see fulltext.]

Original languageEnglish
Article number4
JournalJournal of Clinical Immunology
Issue number1
StatePublished - 19 Dec 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023, The Author(s).


  • LCK
  • T cells
  • TCR signaling
  • combined immunodeficiency
  • diagnosis
  • low CD4 expression


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