Anion exchanger 2 is critical for CD8+ T cells to maintain pHi homeostasis and modulate immune responses

Axel R. Concepcion, January T. Salas, Sarai Sarvide, Elena Sáez, Alex Ferrer, María López, Ainhoa Portu, Jesús M. Banales, Sandra Hervás-Stubbs, Ronald P.J. Oude Elferink, Jesús Prieto, Juan F. Medina

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)1341-1351
Number of pages11
JournalEuropean Journal of Immunology
Issue number5
StatePublished - May 2014


  • AE2 (Slc4a2)
  • IL-2 signals
  • T-cell activation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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