1. Anion exchanger 2 is critical for CD8(+) T cells to maintain pHi homeostasis and modulate immune responses.
- Author
-
Concepcion AR, Salas JT, Sarvide S, Sáez E, Ferrer A, López M, Portu A, Banales JM, Hervás-Stubbs S, Oude Elferink RP, Prieto J, and Medina JF
- Subjects
- Animals, CD4-Positive T-Lymphocytes cytology, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes cytology, CD8-Positive T-Lymphocytes metabolism, Cell Proliferation, Chloride-Bicarbonate Antiporters genetics, Chloride-Bicarbonate Antiporters immunology, Chloride-Bicarbonate Antiporters metabolism, Gene Expression Regulation genetics, Gene Expression Regulation immunology, Hydrogen-Ion Concentration, Interleukin-2 biosynthesis, Interleukin-2 genetics, Interleukin-2 immunology, Interleukin-2 Receptor alpha Subunit biosynthesis, Interleukin-2 Receptor alpha Subunit genetics, Interleukin-2 Receptor alpha Subunit immunology, Ion Transport physiology, Mice, Mice, Knockout, CD8-Positive T-Lymphocytes immunology, Homeostasis physiology, Lymphocyte Activation physiology
- Abstract
Mitogenic stimulation of lymphocytes involves alkalinization of intracellular pH (pHi ). Subsequent pHi regulation may involve HCO3 (-) extrusion through Cl(-) /HCO3 (-) exchangers and/or Na(+) -HCO3 (-) co-transporters with acid-loading capability. Abnormalities in these mechanisms could result in immune dysfunctions, as suggested by the CD8(+) T-cell expansion encountered in mice lacking Ae2 (a widely expressed acid loader with electroneutral and Na(+) -independent Cl(-) /HCO3 (-) anion-exchange activity). Here we report that CD8(+) T cells but not CD4(+) T cells or other lymphocyte populations, are crucially dependent on Ae2 for pHi regulation. While total lymphocytes (including isolated CD4(+) T cells) exhibit Ae1 expression and Na(+) -HCO3 (-) co-transport with acidifying potential, CD8(+) T cells lack these acid-loading mechanisms. In Ae2-KO mice, CD4(+) but not CD8(+) T cells upregulate these potential Ae2 surrogates. As a consequence, Ae2-KO CD8(+) T cells exhibit alkalinized pHi , and dramatically increase their pHi upon CD3 stimulation. Moreover, stimulated Ae2-deficient CD8(+) 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(+) T cells are critically dependent on Ae2 for pHi homeostasis and tuning of cell proliferation and activation. Ae2 thus constitutes a novel target to modulate CD8(+) T-cell responses., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2014
- Full Text
- View/download PDF