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Selective Sparing of Human Tregs by Pharmacologic Inhibitors of the Phosphatidylinositol 3‐Kinase and MEK Pathways
Author(s) -
Zwang N. A.,
Zhang R.,
Germana S.,
Fan M. Y.,
Hastings W. D.,
Cao A.,
Turka L. A.
Publication year - 2016
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.13805
Subject(s) - medicine , phosphatidylinositol , kinase , pharmacology , cancer research , immunology , microbiology and biotechnology , biology
Phosphatidylinositol 3‐kinase ( PI 3K) and mitogen‐activated protein kinase/extracellular signal‐regulated ( MEK ) signaling are central to the survival and proliferation of many cell types. Multiple lines of investigation in murine models have shown that control of the PI 3K pathway is particularly important for regulatory T cell (Treg) stability and function. PI 3K and MEK inhibitors are being introduced into the clinic, and we hypothesized that pharmacologic inhibition of PI 3K, and possibly MEK , in mixed cultures of human mononuclear cells would preferentially affect CD 4 + and CD 8 + lymphocytes compared with Tregs. We tested this hypothesis using four readouts: proliferation, activation, functional suppression, and signaling. Results showed that Tregs were less susceptible to inhibition by both δ and α isoform–specific PI 3K inhibitors and by an MEK inhibitor compared with their conventional CD 4 + and CD 8 + counterparts. These studies suggest less functional reliance on PI 3K and MEK signaling in Tregs compared with conventional CD 4 + and CD 8 + lymphocytes. Therefore, the PI 3K and MEK pathways are attractive pharmacologic targets for transplantation and treatment of autoimmunity.