Abstract
Store-operated Ca(2+) entry (SOCE) is an essential process in T cell activation. SOCE is controlled by the Ca(2+) release-activated Ca(2+) (CRAC) channel encoded by the gene Orai1 that is expressed on the plasma membrane and activated by STIM1 when ER Ca(2+) stores are depleted. Our earlier work showed that a somatic T-cell line Jurkat mutant H123 bearing a defect in Ca(2+) signaling was susceptible to the apoptotic effects of type I interferons (IFN-α/β). The nature of the mutation and whether this mutation was linked to IFN-α/β apoptotic susceptibility was unknown. Here we show that H123 cells lacked Orai1 and exhibit reduced STIM1 protein. Reconstitution of both Orai1 and STIM1 in H123 cells rescued SOCE in response to thapsigargin and ionomycin and abrogated IFN-α/β-induced apoptosis. Reciprocally, overexpression of the dominant negative Orai1-E106A in either parental Jurkat cells or an unrelated human T cell line (CEM391) inhibited SOCE and led to sensitization to IFN-α/β-induced apoptosis. Furthermore, we showed that the Ca(2+) response pathway antagonized the IFN-α/β -induced transcriptional responses; in the absence of SOCE, this negative regulatory effect was lost. However, the inhibitory effect of Ca(2+) on type I IFN-induced gene transcription was diminished by pharmacological inhibition of NF-κB in cells with intact SOCE. Our findings reveal an unexpected and novel regulatory crosstalk mechanism between type I IFNs and store-operated Ca(2+) signaling pathways mediated at least in part by NF-κB activity with significant clinical implications to both viral and tumor immunology.
Highlights
Type I interferons are immunomodulatory cytokines that either prevent or promote apoptosis of T cells
Impaired Store-operated Ca2؉ entry (SOCE) in Somatic Jurkat Variant H123—Chemical mutagenesis of the human T-cell line Jurkat with the ICR-191 frameshift mutagen has led to the identification of a number of critical signaling molecules needed in T cell activation [9, 22]
What remained unclear was whether this gain of apoptotic function induced by IFN-␣/ in H123 cells was intimately linked to a defect in the Ca2ϩ response pathway
Summary
Type I interferons are immunomodulatory cytokines that either prevent or promote apoptosis of T cells. Results: Loss of Orai1-mediated Ca2ϩ entry sensitizes T cells to type I interferon-induced apoptosis via NF-B activity. Our earlier work showed that a somatic T-cell line Jurkat mutant H123 bearing a defect in Ca2؉ signaling was susceptible to the apoptotic effects of type I interferons (IFN-␣/). The antiproliferative effects of IFN-␣ in T cells required Lck, Zap, and CD45, all components of the TCR signal transduction pathway [7] These studies were conducted using both somatic mutants of human. When ER Ca2ϩ stores are depleted, STIM proteins aggregate and make contact with the plasma membrane This in turn results in the opening of the Orai channel, leading to extended elevation of cytosolic Ca2ϩ levels, which triggers Ca2ϩ-dependent signaling responses. Defective SOCE Alters IFN Responses all, our data indicate a novel role for SOCE in antagonizing the apoptotic and transcriptional activities of type I IFNs
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