title: Cutting edge: Foxp3-mediated induction of pim 2 allows human T regulatory cells to preferentially expand in rapamycin.
abstract: Addition of rapamycin to cultures of expanding natural CD4+CD25+Foxp3+ T regulatory cells (Tregs) helps maintain their suppressive activity, but the underlying mechanism is unclear. Pim 2 is a serine/threonine kinase that can confer rapamycin resistance. Unexpectedly, pim 2 was found to be constitutively expressed in freshly isolated, resting Tregs, but not in CD4+CD25- T effector cells. Introduction of Foxp3, but not Foxp3Delta2, into effector T cells induced pim 2 expression and conferred preferential expansion in the presence of rapamycin, indicating that Foxp3 can regulate pim 2 expression. Finally, we determined there is a positive correlation between Treg expansion and Foxp3 expression in the presence of rapamycin. Together, these results indicate that Tregs are programmed to be resistant to rapamycin, providing further rationale for why this immunosuppressive drug should be used in conjunction with expanded Tregs.
authors.affiliation: Abramson Family Cancer Research Institute and Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Samik
authors.initials: S
authors.lastname: Basu
authors.forename: Tatiana
authors.initials: T
authors.lastname: Golovina
authors.forename: Tatiana
authors.initials: T
authors.lastname: Mikheeva
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
authors.forename: James L
authors.initials: JL
authors.lastname: Riley
mesh_terms: D004351:Drug Resistance / Q000187:drug effects / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000276:immunology* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000276:immunology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000276:immunology*; D020123:Sirolimus / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007166:Immunosuppressive Agents; C490587:PIM2 protein, human; D011518:Proto-Oncogene Proteins; D017346:Protein Serine-Threonine Kinases; D020123:Sirolimus