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ORAI1 deficiency impairs activated T cell death and enhances T cell survival
- Publication Year :
- 2011
-
Abstract
- ORAI1 is a pore subunit of Ca2+ release-activated Ca2+ channels that mediate TCR stimulation-induced Ca2+ entry. A point mutation in ORAI1 (ORAI1R91W) causes SCID in human patients that is recapitulated in Orai1−/− mice, emphasizing its important role in the immune cells. In this study, we have characterized a novel function of ORAI1 in T cell death. CD4+ T cells from Orai1−/− mice showed robust proliferation with repetitive stimulations and strong resistance to stimulation-induced cell death due to reduced mitochondrial Ca2+ uptake and altered gene expression of proapoptotic and antiapoptotic molecules (e.g., Fas ligand, Noxa, and Mcl-1). Nuclear accumulation of NFAT was severely reduced in ORAI1-deficient T cells, and expression of ORAI1 and a constitutively active mutant of NFAT recovered cell death. These results indicate NFAT-mediated cell death pathway as one of the major downstream targets of ORAI1-induced Ca2+ entry. By expressing various mutants of ORAI1 in wild-type and Orai1−/− T cells to generate different levels of intracellular Ca2+, we have shown that activation-induced cell death is directly proportional to the intracellular Ca2+ concentration levels. Consistent with the in vitro results, Orai1−/− mice showed strong resistance to T cell depletion induced by injection of anti-CD3 Ab. Furthermore, ORAI1-deficient T cells showed enhanced survival after adoptive transfer into immunocompromised hosts. Thus, our results demonstrate a crucial role of the ORAI1–NFAT pathway in T cell death and highlight the important role of ORAI1 as a major route of Ca2+ entry during activated T cell death.
- Subjects :
- CD4-Positive T-Lymphocytes
Adoptive cell transfer
Programmed cell death
ORAI1 Protein
Cell Survival
T cell
Immunology
Immunoblotting
Apoptosis
Cell Separation
Biology
Fas ligand
Article
Mice
Immune system
Transduction, Genetic
medicine
Immunology and Allergy
Cytotoxic T cell
Animals
Humans
Calcium Signaling
Mice, Knockout
NFATC Transcription Factors
Reverse Transcriptase Polymerase Chain Reaction
T-cell receptor
NFAT
Flow Cytometry
Molecular biology
Cell biology
Mitochondria
medicine.anatomical_structure
Calcium Channels
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....fc5a6c49f23cf69798a22eb75c5336af