title: Anion exchanger 2 is critical for CD8(+) T cells to maintain pHi homeostasis and modulate immune responses.
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.
authors: Center for Applied Medical Research (CIMA), Clinic and School of Medicine University of Navarra, Pamplona, Spain; CIBERehd, the "Carlos III" Institute of Health, Madrid, Spain.
authors: Axel R
authors: AR
authors: Concepcion
authors: January T
authors: JT
authors: Salas
authors: Sarai
authors: S
authors: Sarvide
authors: Elena
authors: E
authors: Sáez
authors: Alex
authors: A
authors: Ferrer
authors: María
authors: M
authors: López
authors: Ainhoa
authors: A
authors: Portu
authors: Jesús M
authors: JM
authors: Banales
authors: Sandra
authors: S
authors: Hervás-Stubbs
authors: Ronald P J
authors: RP
authors: Oude Elferink
authors: Jesús
authors: J
authors: Prieto
authors: Juan F
authors: JF
authors: Medina
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D027963:Chloride-Bicarbonate Antiporters / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D006706:Homeostasis / Q000502:physiology*; D006863:Hydrogen-Ion Concentration; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D017136:Ion Transport / Q000502:physiology; D008213:Lymphocyte Activation / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D027963:Chloride-Bicarbonate Antiporters; C508018:Il2ra protein, mouse; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; C579495:Slc4a2 protein, mouse
keywords: AE2 (Slc4a2); IL-2 signals; T-cell activation