Combined Immunodeficiency Caused by a Novel Nonsense Mutation in LCK

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

Helper T cell immunity in humans with inherited CD4 deficiency

“…Recent studies in humans identified patients with partial or complete LCK deficiency. Interestingly, CD4 expression was decreased in T cells from LCK deficient patients, suggesting that recruited LCK plays a crucial role in stabilizing CD4 on the surface of T cells ( Keller et al, 2023 ; Lanz et al, 2023 ; Lui et al, 2024 ). CD4-mediated interactions with CD3 increase the duration of cognate TCR–HLA class II interplay and therefore ensure scalable signaling which determines the duration and magnitude of responses of CD4 + T cells ( Glassman et al, 2018 ).…”