Combined Immunodeficiency Caused by a Novel Nonsense Mutation in LCK

AbstractMutations 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 inLCK 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.ResultsBoth patients primarily presented with infections in early infancy. TheLCK 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 na ïve 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 par tially 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-c...
Source: Journal of Clinical Immunology - Category: Allergy & Immunology Source Type: research