Water channel Aquaporin 4 is required for T cell activation

• Published in: The Journal of immunology (1950) Vol. 210; no. 1_Supplement; pp. 173 - 173.07
• Main Authors: Nicosia, Michael, Beavers, Ashley, Kish, Danielle, Farr, George W, McGuirk, Paul R, Pelletier, Marc F, Fairchild, Robert L, Valujskikh, Anna
• Format: Journal Article
• Language: English
• Published: 01.05.2023
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.210.Supp.173.07

Abstract Aquaporins are a family of ubiquitously expressed transmembrane water channels. We have previously reported that Aquaporin 4 (AQP4) is expressed on T cells and that treatment with a small molecule AQP4 inhibitor significantly delays T cell mediated heart allograft rejection. The goal of this study was to identify mechanisms of prolonged graft survival following AQP4 blockade. Stimulation of murine WT T cells + AER-270 or AQP4 −/−T cells resulted in decreased expression of T cell activation markers CD25 and CD44, and reduced cell volume when compared to control WT T cells. In addition, the absence or inhibition of AQP4 also limited IL-2 production by T cells following stimulation. Intact AQP4 was also required for optimal IFNg production by T cells. Analogously, AQP4 inhibition significantly limited the ability of human T cells to proliferate following TCR stimulation. We then examined the role of AQP4 in TCR signal transduction and found that AQP4 was required for nuclear translocation of NF-KB and NFAT and for optimal calcium flux following TCR stimulation. Either the absence or inhibition of AQP4 impaired TCR signal transduction as early as phosphorylation of Lck (pY394), ZAP70 (pY319) and LAT (p171). AQP4 was previously shown to associate with the actin cytoskeleton in other cell types, we next tested its involvement in TCR polarization/capping. We found that loss of AQP4 resulted in significantly impaired TCR capping and dysfunctional post-TCR stimulation actin remodeling kinetics. Our findings reveal novel mechanisms underlying the importance of AQP4 in optimal T lymphocyte activation and identify AQP4 as a potential therapeutic target for preventing TCR-mediated T cell activation in solid organ transplantation and other diseases.