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

Mitogenic stimulation of lymphocytes involves alkalinization of intracellular pH (pH_i). Subsequent pH_i 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 pH_i 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 pH_i, and dramatically increase their pH_i 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 pH_i homeostasis and tuning of cell proliferation and activation. Ae2 thus constitutes a novel target to modulate CD8⁺ T-cell responses.