In this study, Sharma et al. demonstrate that reduced methionine availability early during T cell activation drives CD8 T cells towards exhaustion in both infection and tumor models in mice. These effects were attributed to reduced methylation of an arginine residue in the K+ channel KCa3.1 and its increased activity, resulting in enhanced calcium influx and NFAT1 activation. Methylation of Arg350 weakens the interaction of KCa3.1 with calmodulin and may represent a mechanism to prevent T cell hyperactivation. -HW
In this study, Li et al. report that that serotonin transporter (SERT) inhibits CD8 T cell antitumor immunity by depleting intratumoral serotonin. SERT-blocking SSRI antidepressants enhance CD8 T cell function and synergize with anti-PD-1 therapy, suggesting SSRIs as potential cancer immunotherapeutics. –HYC/ZQ
The study shows that the mechanosensitive ion channel Piezo1 acts as a negative regulator of group 2 innate lymphoid cells (ILC2s) and their role in airway hyperreactivity (AHR) in allergic asthma. Whereas deletion of Piezo1 augments ILC2 activity and AHR, agonist mediated Piezo1 activation suppresses ILC2-driven AHR suggesting that Piezo1 agonists could have therapeutic potential in asthma. –WAC
Zhong et al. report that store-operated Ca2+ entry (SOCE) activated by STIM1 and mediated by ORAI channels is required for the differentiation of Th1 cells, which are crucial for immunity against intracellular pathogens. SOCE synergizes with IFN-γ induced STAT1 signaling to promote expression of the Th1 transcription factor T-bet. Loss of STIM1 impairs Th1 differentiation, particularly when the cytokine IL-12 is absent. As many viruses do not induce IL-12 production and IL-12 production is low in infants, these findings highlight the importance of SOCE in early life immune responses. –HYC/SF
Doyle et al. demonstrate that TRPM7 ion channel activity is essential for acidification of virus-containing endosomes by providing a cationic countercurrent that enables sustained V-ATPase proton pumping, with loss or pharmacological inhibition of TRPM7 preventing infection by pH-dependent enveloped viruses (Lassa, LCMV, Ebola, SARS-CoV-2, influenza) but not pH-independent viruses (VSV, rabies). This positions TRPM7 as a potential broad-spectrum antiviral target, as its channel activity specifically regulates the acidification of virus-laden endosomes without affecting general endosomal function, and pharmacological inhibition protected mice from influenza infection in vivo. –BD
This study shows that the Kir6.1 subunit of a type of ATP-sensitive potassium (KATP) channels is highly expressed in murine NK cells and that NK cells express a current sensitive to a Kir6.1 blocker. NK cell specific knockout of Kcnj8 (encoding Kir6.1) attenuates NK cell maturation, but has no effect on NK cell degranulation, IFN-γ release and tumor cell killing. –WAC
This study identifies LRRC8C as a novel transporter for cyclic dinucleotides (CDNs) in T cells demonstrating that: i) LRRC8C expression is induced by IL-2 signaling in T cells, ii) LRRC8C facilitates influx of CDNs such as cGAMP, activating the CDN sensor STING, iii) STING activation results in p53 accumulation, causing cell cycle arrest and apoptosis. This study establishes the LRRC8C–STING–p53 axis as a negative feedback pathway suppressing T cell responses and adaptive immunity. –ARC/SF
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