Anion exchanger 2 is critical for CD8+ T cells to maintain pHi homeostasis and modulate immune responses. Issue 5 (11th March 2014)

• Record Type: Journal Article
• Authors: Concepcion, Axel R.; Salas, January T.; Sarvide, Sarai; Sáez, Elena; Ferrer, Alex; López, María; Portu, Ainhoa; Banales, Jesús M.; Hervás‐Stubbs, Sandra; Oude Elferink, Ronald P. J.; Prieto, Jesús; Medina, Juan F.
• Is Part Of: European journal of immunology. Volume 44:Issue 5(2014:May)
• Page Start: 1341
• Page End: 1351
• Publication Date: 2014-03-11
• Subjects: Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201344218
• Languages: English
• ISSNs: 0014-2980

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Mitogenic stimulation of lymphocytes involves alkalinization of intracellular pH (pH<sub>i</sub>). Subsequent pH<sub>i</sub> regulation may involve HCO<sub>3</sub><sup>−</sup> extrusion through Cl<sup>−</sup>/HCO<sub>3</sub><sup>−</sup> exchangers and/or Na<sup>+</sup>‐HCO<sub>3</sub><sup>−</sup> co‐transporters with acid‐loading capability. Abnormalities in these mechanisms could result in immune dysfunctions, as suggested by the CD8<sup>+</sup> T‐cell expansion encountered in mice lacking Ae2 (a widely expressed acid loader with electroneutral and Na<sup>+</sup>‐independent Cl<sup>−</sup>/HCO<sub>3</sub><sup>−</sup> anion‐exchange activity). Here we report that CD8<sup>+</sup> T cells but not CD4<sup>+</sup> T cells or other lymphocyte populations, are crucially dependent on Ae2 for pH<sub>i</sub> regulation. While total lymphocytes (including isolated CD4<sup>+</sup> T cells) exhibit Ae1 expression and Na<sup>+</sup>‐HCO<sub>3</sub><sup>−</sup> co‐transport with acidifying potential, CD8<sup>+</sup> T cells lack these acid‐loading mechanisms. In Ae2‐KO mice, CD4<sup>+</sup> but not CD8<sup>+</sup> T cells upregulate these potential Ae2 surrogates. As a consequence, Ae2‐KO CD8<sup>+</sup> T cells exhibit alkalinized pH<sub>i</sub>, and dramatically increase their pH<sub>i</sub> upon CD3 stimulation. Moreover, stimulated Ae2‐deficient CD8<sup>+</sup> T cells show enhanced intracellular production of IL‐2 and membrane expression of its receptor IL‐2Rα, together with increased cell proliferation and activation. These findings demonstrate that CD8<sup>+</sup> T cells are critically dependent on Ae2 for pH<sub>i</sub> homeostasis and tuning of cell proliferation and activation. Ae2 thus constitutes a novel target to modulate CD8<sup>+</sup> T‐cell responses.</p> </abstract>