Disrupted Ca2+ Homeostasis and Immunodeficiency in Patients With Functional Ip3 Receptor Subtype 3 Defects

Authors

Julika Neumann
Erika Van Nieuwenhove
Lara E Terry
Frederik Staels
Taylor R Knebel
Kirsten Welkenhuyzen
Kourosh Ahmadzadeh
Mariah R Baker
Margaux Gerbaux
Mathijs Willemsen
John S Barber
Irina I Serysheva
Liesbeth De Waele
François Vermeulen
Susan Schlenner
Isabelle Meyts
David I Yule
Geert Bultynck
Rik Schrijvers
Stephanie Humblet-Baron
Adrian Liston

Publication Date

1-1-2023

Journal

Cellular & Molecular Immunology

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 (IP3R), a homo- or heterotetramer of the IP3R1-3 isoforms, amplifies lymphocyte signaling by releasing Ca2+ from endoplasmic reticulum stores following antigen stimulation. Although knockout of all IP3R 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 IP3R 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 IP3R3 in IP3R 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 IP3Rs 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.

Keywords

Primary immunodeficiency, Calcium signalling, Whole exome sequencing, Adaptive immunity, Primary immunodeficiency disorders, Calcium signaling, Immunogenetics

Comments

Author Correction: Disrupted Ca2+ homeostasis and immunodeficiency in patients with functional IP3 receptor subtype 3 defects>.