Dominant negative variants in ITPR3 impair T cell Ca2+ dynamics causing combined immunodeficiency

Area of Science:

• Immunology
• Cell Biology
• Genetics

Background:

• Calcium (Ca2+) influx via store-operated Ca2+ entry (SOCE) is critical for T cell signaling and immune function.
• Deficiencies in STIM1 and ORAI1, key regulators of SOCE, lead to combined immunodeficiency (CID).

Purpose of the Study:

• To investigate the role of inositol 1,4,5-trisphosphate receptor (IP3R) in T cell signaling and its association with combined immunodeficiency (CID).

Main Methods:

• Genetic analysis of five unrelated patients with de novo missense variants in ITPR3.
• Assessment of T cell calcium homeostasis, development, and function.
• Evaluation of endoplasmic reticulum (ER) Ca2+ stores and SOCE.

Main Results:

• Identified de novo missense variants in ITPR3 in patients presenting with CID, abnormal T cell Ca2+ homeostasis, ectodermal dysplasia, and multisystem disease.
• Observed significant T cell lymphopenia, impaired thymic T cell development, and defective peripheral T cell responses (NF-κB, NFAT, proliferation, metabolism).
• Demonstrated that ITPR3 variants impair IP3R channel function, leading to ER Ca2+ depletion and blunted SOCE in T cells.

Conclusions:

• De novo variants in ITPR3 cause a distinct form of combined immunodeficiency (CID) by disrupting T cell calcium signaling.
• ITPR3 variants lead to impaired T cell development and function through defective ER Ca2+ release and blunted SOCE.
• This study highlights the crucial role of IP3R-mediated calcium release in T cell immunity and overall health.