科研之友
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摘要
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(+) Tcells but not CD4(+) Tcells or other lymphocyte populations, are crucially dependent on Ae2 for pH(i) regulation. While total lymphocytes (including isolated CD4(+) Tcells) exhibit Ae1 expression and Na+-HCO3- co-transport with acidifying potential, CD8(+) Tcells lack these acid-loading mechanisms. In Ae2-KO mice, CD4(+) but not CD8(+) Tcells upregulate these potential Ae2 surrogates. As a consequence, Ae2-KO CD8(+) Tcells exhibit alkalinized pH(i), and dramatically increase their pH(i) upon CD3 stimulation. Moreover, stimulated Ae2-deficient CD8(+) Tcells show enhanced intracellular production of IL-2 and membrane expression of its receptor IL-2R, together with increased cell proliferation and activation. These findings demonstrate that CD8(+) Tcells 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.
- 出版日期2014-5
