Related Experiment Video

Updated: Jun 7, 2025

In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
00:06

In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila

Published on: August 20, 2019

13.6K

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

Elena Blanco1, Carme Camps2,3, Sameer Bahal1

  • 1Molecular and Cellular Immunology, Great Ormond Street Institute of Child Health, University College London , London, UK.

The Journal of Experimental Medicine
|November 19, 2024
PubMed

Insights

Genetic variants in ITPR3 cause combined immunodeficiency (CID) by disrupting calcium (Ca2+) signaling in T cells. This impairs T cell development and function, leading to immune system defects and multisystem disease.

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.

More Related Videos

Characterization of Thymus-dependent and Thymus-independent Immunoglobulin Isotype Responses in Mice Using Enzyme-linked Immunosorbent Assay06:15

Characterization of Thymus-dependent and Thymus-independent Immunoglobulin Isotype Responses in Mice Using Enzyme-linked Immunosorbent Assay

Published on: September 7, 2018

9.4K
Isolation of Double Negative αβ T Cells from the Kidney06:56

Isolation of Double Negative αβ T Cells from the Kidney

Published on: May 16, 2014

12.3K

Related Concept Videos

Immunodeficiency Diseases01:25

Immunodeficiency Diseases

Immunodeficiency disorders are conditions in which the immune system's ability to fight infectious disease and cancer is compromised or entirely absent. The immune system comprises a complex network of cells, tissues, and organs that work together to protect the body from potentially harmful invaders. When this system is deficient or not functioning properly, it leaves the body susceptible to infections, diseases, or other complications.
There are three main causes of immunodeficiency...
909
Incomplete Dominance01:43

Incomplete Dominance

Gregor Mendel's work (1822 - 1884) was primarily focused on pea plants. Through his initial experiments, he determined that every gene in a diploid cell has two variants called alleles inherited from each parent. He suggested that amongst these two alleles, one allele is dominant in character and the other recessive. The combination of alleles determines the phenotype of a gene in an organism.
21.6K
T Cell Types and Functions01:24

T Cell Types and Functions

When T cells with CD4 markers are activated, they give rise to two types of effector cells: helper T cells and regulatory T cells. Meanwhile, T cells with CD8 markers differentiate into effector cytotoxic T cells. The differentiation of CD4 T cells into helper T cell subsets, such as Th1, Th2, and Th17 cells, is dependent on the antigen type, antigen-presenting cell, and regulatory cytokines.
Th1 cells stimulate dendritic cells to express necessary co-stimulatory molecules on their surfaces for...
954