Lymphocyte populations with different sensitivity to cyclosporin have different plasma membrane potentials

Cyclosporin A (CsA), a clinically potent immunosuppressive agent, shows preferential biologic activity against certain lymphocyte subsets. To investigate this activity, we used flow cytometry to separate two distinct lymphocyte populations from unfractionated human peripheral blood lymphocytes, based on their different binding affinity for a biologically active fluorescent, dansylated cyclosporin (dans-CsA) derivative. The separate lymphocyte populations demonstrated different resting plasma membrane potentials. The two lymphocyte populations also had different levels of interleukin-2 (IL-2) receptors and shifted plasma membrane potential differently upon treatment with cyclosporin and lymphokine IL-2. The cell population that bound more dans-CsA contained the cells which possessed IL-2 receptors and responded to CsA and IL-2 with changes in membrane potential. The cell population that did not effectively bind dans-CsA lacked IL-2 receptors and did not respond to CsA or IL-2 with immediate membrane potential changes. Furthermore, stimulation studies of these separated two lymphocyte populations with phytohemagglutinin in the presence and absence of CsA revealed that only the population which binds a low level of dans-CsA shows a marked difference in membrane potential between the cells stimulated in the presence and absence of CsA. We concluded that ion flux changes caused by CsA affect the activation process of naive lymphocytes but not that of already stimulated ones. It can also be postulated that the ion flux changing property of CsA could constitute its primary or main mode of action.