Trpm4 differentially regulates Th1 and Th2 function by altering calcium signaling and NFAT localization.
Th cell subsets have unique calcium (Ca(2+)) signals when activated with identical stimuli. The regulation of these Ca(2+) signals and their correlation to the biological function of each T cell subset remains unclear. Trpm4 is a Ca(2+)-activated cation channel that we found is expressed at higher levels in Th2 cells compared with Th1 cells. Inhibition of Trpm4 expression increased Ca(2+) influx and oscillatory levels in Th2 cells and decreased influx and oscillations in Th1 cells. This inhibition of Trpm4 expression also significantly altered T cell cytokine production and motility. Our experiments revealed that decreasing Trpm4 levels divergently regulates nuclear localization of NFATc1. Consistent with this, gene profiling did not show Trpm4-dependent transcriptional regulation, and T-bet and GATA-3 levels remain identical. Thus, Trpm4 is expressed at different levels in Th cells and plays a distinctive role in T cell function by differentially regulating Ca(2+) signaling and NFATc1 localization.
Weber
K Scott
KS
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Hildner
Kai
K
Murphy
Kenneth M
KM
Allen
Paul M
PM
D000818:Animals; D002118:Calcium / Q000037:antagonists & inhibitors / Q000502:physiology; D020013:Calcium Signaling / Q000235:genetics / Q000276:immunology*; D002413:Cations, Divalent / Q000037:antagonists & inhibitors / Q000378:metabolism; D002464:Cell Migration Inhibition / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000276:immunology; D051379:Mice; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics / Q000276:immunology; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
D002413:Cations, Divalent; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D050053:TRPM Cation Channels; C476766:TRPM4 protein, mouse; D002118:Calcium