학술논문
Disrupted Ca2+ homeostasis and immunodeficiency in patients with functional IP3 receptor subtype 3 defects
Document Type
Original Paper
Author
Neumann, Julika; Van Nieuwenhove, Erika; Terry, Lara E.; Staels, Frederik; Knebel, Taylor R.; Welkenhuyzen, Kirsten; Ahmadzadeh, Kourosh; Baker, Mariah R.; Gerbaux, Margaux; Willemsen, Mathijs; Barber, John S.; Serysheva, Irina I.; De Waele, Liesbeth; Vermeulen, François; Schlenner, Susan; Meyts, Isabelle; Yule, David I.; Bultynck, Geert; Schrijvers, Rik; Humblet-Baron, Stephanie; Liston, Adrian
Source
Cellular & Molecular Immunology. 20(1):11-25
Subject
Language
English
ISSN
2042-0226
Abstract
Calcium signaling is essential for lymphocyte activation, with genetic disruptions of store-operated calcium (Ca2+ ) entry resulting in severe immunodeficiency. The inositol 1,4,5-trisphosphate receptor (IP3 R), a homo- or heterotetramer of the IP3 R1-3 isoforms, amplifies lymphocyte signaling by releasing Ca2+ from endoplasmic reticulum stores following antigen stimulation. Although knockout of all IP3 R isoforms in mice causes immunodeficiency, the seeming redundancy of the isoforms is thought to explain the absence of variants in human immunodeficiency. In this study, we identified compound heterozygous variants of ITPR3 (a gene encoding IP3 R subtype 3) in two unrelated Caucasian patients presenting with immunodeficiency. To determine whether ITPR3 variants act in a nonredundant manner and disrupt human immune responses, we characterized the Ca2+ signaling capacity, the lymphocyte response, and the clinical phenotype of these patients. We observed disrupted Ca2+ signaling in patient-derived fibroblasts and immune cells, with abnormal proliferation and activation responses following T-cell receptor stimulation. Reconstitution of IP3 R3 in IP3 R knockout cell lines led to the identification of variants as functional hypomorphs that showed reduced ability to discriminate between homeostatic and induced states, validating a genotype–phenotype link. These results demonstrate a functional link between defective endoplasmic reticulum Ca2+ channels and immunodeficiency and identify IP3 Rs as diagnostic targets for patients with specific inborn errors of immunity. These results also extend the known cause of Ca2+ -associated immunodeficiency from store-operated entry to impaired Ca2+ mobilization from the endoplasmic reticulum, revealing a broad sensitivity of lymphocytes to genetic defects in Ca2+ signaling.