title: Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells.
abstract: Rapamycin is an immunosuppressive compound that is currently used to prevent acute graft rejection in humans. In addition, rapamycin has been shown to allow operational tolerance in murine models. However, a direct effect of rapamycin on T regulatory (Tr) cells, which play a key role in induction and maintenance of peripheral tolerance, has not been demonstrated so far. Here, we provide new evidence that rapamycin selectively expands the murine naturally occurring CD4(+)CD25(+)FoxP3(+) Tr cells in vitro. These expanded Tr cells suppress proliferation of syngeneic T cells in vitro and prevent allograft rejection in vivo. Interestingly, rapamycin does not block activation-induced cell death and proliferation of CD4(+) T cells in vitro. Based on this new mode of action, rapamycin can be used to expand CD4(+)CD25(+)FoxP3(+) Tr cells for ex vivo cellular therapy in T-cell-mediated diseases.
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Battaglia
authors.forename: Angela
authors.initials: A
authors.lastname: Stabilini
authors.forename: Maria-Grazia
authors.initials: MG
authors.lastname: Roncarolo
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects*; D018929:Cell Culture Techniques / Q000379:methods*; D016923:Cell Death; D049109:Cell Proliferation; D002469:Cell Separation; D002478:Cells, Cultured; D018920:Coculture Techniques; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007108:Immune Tolerance; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016381:Islets of Langerhans Transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis*; D020123:Sirolimus / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007166:Immunosuppressive Agents; D015375:Receptors, Interleukin-2; D020123:Sirolimus