title: Selective Sparing of Human Tregs by Pharmacologic Inhibitors of the Phosphatidylinositol 3-Kinase and MEK Pathways.
abstract: Phosphatidylinositol 3-kinase (PI3K) 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 PI3K pathway is particularly important for regulatory T cell (Treg) stability and function. PI3K and MEK inhibitors are being introduced into the clinic, and we hypothesized that pharmacologic inhibition of PI3K, and possibly MEK, in mixed cultures of human mononuclear cells would preferentially affect CD4(+) and CD8(+) 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 PI3K inhibitors and by an MEK inhibitor compared with their conventional CD4(+) and CD8(+) counterparts. These studies suggest less functional reliance on PI3K and MEK signaling in Tregs compared with conventional CD4(+) and CD8(+) lymphocytes. Therefore, the PI3K and MEK pathways are attractive pharmacologic targets for transplantation and treatment of autoimmunity.
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA.|Massachusetts General Hospital/Brigham and Women's Hospital Nephrology Joint Fellowship Program, Boston, MA.
authors.forename: N A
authors.initials: NA
authors.lastname: Zwang
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA.
authors.forename: R
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA.
authors.forename: S
authors.initials: S
authors.lastname: Germana
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA.
authors.forename: M Y
authors.initials: MY
authors.lastname: Fan
authors.affiliation: Novartis Pharmaceuticals, Cambridge, MA.
authors.forename: W D
authors.initials: WD
authors.lastname: Hastings
authors.affiliation: Novartis Pharmaceuticals, Cambridge, MA.
authors.forename: A
authors.initials: A
authors.lastname: Cao
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA.
authors.forename: L A
authors.initials: LA
authors.lastname: Turka
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D048369:MAP Kinase Kinase 1
keywords: T cell biology; immunosuppression/immune modulation; signaling/signaling pathways: PI-3 kinase/Akt pathway; translational research/science