title: The role of 2 FOXP3 isoforms in the generation of human CD4+ Tregs.
abstract: Little is known about the molecules that control the development and function of CD4+ CD25+ Tregs. Recently, it was shown that the transcription factor FOXP3 is necessary and sufficient for the generation of CD4+ CD25+ Tregs in mice. We investigated the capacity of FOXP3 to drive the generation of suppressive CD4+ CD25+ Tregs in humans. Surprisingly, although ectopic expression of FOXP3 in human CD4+ T cells resulted in induction of hyporesponsiveness and suppression of IL-2 production, it did not lead to acquisition of significant suppressor activity in vitro. Similarly, ectopic expression of FOXP3delta2, an isoform found in human CD4+ CD25+ Tregs that lacks exon 2, also failed to induce the development of suppressor T cells. Moreover, when FOXP3 and FOXP3delta2 were simultaneously overexpressed, although the expression of several Treg-associated cell surface markers was significantly increased, only a modest suppressive activity was induced. These data indicate that in humans, overexpression of FOXP3 alone or together with FOXP3delta2 is not an effective method to generate potent suppressor T cells in vitro and suggest that factors in addition to FOXP3 are required during the process of activation and/or differentiation for the development of bona fide Tregs.
authors.affiliation: Department of Surgery, University of British Columbia, and Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Allan
authors.forename: Laura
authors.initials: L
authors.lastname: Passerini
authors.forename: Rosa
authors.initials: R
authors.lastname: Bacchetta
authors.forename: Natasha
authors.initials: N
authors.lastname: Crellin
authors.forename: Minyue
authors.initials: M
authors.lastname: Dai
authors.forename: Paul C
authors.initials: PC
authors.lastname: Orban
authors.forename: Steven F
authors.initials: SF
authors.lastname: Ziegler
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Roncarolo
authors.forename: Megan K
authors.initials: MK
authors.lastname: Levings
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000235:genetics; D009154:Mutation; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D020033:Protein Isoforms