title: Rapamycin-mediated enrichment of T cells with regulatory activity in stimulated CD4+ T cell cultures is not due to the selective expansion of naturally occurring regulatory T cells but to the induction of regulatory functions in conventional CD4+ T cells.
abstract: Rapamycin is an immunosuppressive drug currently used in different clinical settings. Although the capacity of rapamycin to inhibit the mammalian target of rapamycin serine/threonine protein kinase and therefore T cell cycle progression is well known, its effects are complex and not completely understood. It has been reported recently that TCR-mediated stimulation of murine CD4+ T cells in the presence of rapamycin results in increased proportions of CD4+ T cells with suppressive functions, suggesting that the drug may also exert its immunosuppressive activity by promoting the selective expansion of naturally occurring CD4+ regulatory T cells (Treg). In this study, we show that stimulation of human circulating CD4+ T cells in the presence of rapamycin results indeed in highly increased suppressor activity. By assessing the effect of rapamycin on the growth of nonregulatory and Treg populations of defined differentiation stages purified ex vivo from circulating CD4+ T cells, we could demonstrate that this phenomenon is not due to a selective expansion of naturally occurring Tregs, but to the capacity of rapamycin to induce, upon TCR-mediated stimulation, suppressor functions in conventional CD4+ T cells. This condition, however, is temporary and reversible as it is dependent upon the continuous presence of rapamycin.
authors.affiliation: Ludwig Institute Clinical Trial Center, Department of Medicine, Columbia University College of Physicians and Surgeons, Black Building 20-09, 650 West 168th Street, New York, NY 10032, USA. msa2106@columbia.edu
authors.forename: Danila
authors.initials: D
authors.lastname: Valmori
authors.forename: Valeria
authors.initials: V
authors.lastname: Tosello
authors.forename: Naira E
authors.initials: NE
authors.lastname: Souleimanian
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Godefroy
authors.forename: Luigi
authors.initials: L
authors.lastname: Scotto
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Maha
authors.initials: M
authors.lastname: Ayyoub
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000187:drug effects*; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D020123:Sirolimus / Q000494:pharmacology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D017252:CD3 Complex; D006131:Growth Inhibitors; D015375:Receptors, Interleukin-2; D020123:Sirolimus