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- Title
Combined Immunodeficiency Caused by a Novel Nonsense Mutation in LCK.
- Authors
Keller, Baerbel; Kfir-Erenfeld, Shlomit; Matusewicz, Paul; Hartl, Frederike; Lev, Atar; Lee, Yu Nee; Simon, Amos J.; Stauber, Tali; Elpeleg, Orly; Somech, Raz; Stepensky, Polina; Minguet, Susana; Schraven, Burkhart; Warnatz, Klaus
- 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.
- Publication
Journal of Clinical Immunology, 2024, Vol 44, Issue 1, p1
- ISSN
0271-9142
- Publication type
Article
- DOI
10.1007/s10875-023-01614-4