title: Rapamycin combined with TGF-β converts human invariant NKT cells into suppressive Foxp3+ regulatory cells.
abstract: Invariant NKT (iNKT) cells constitute a versatile T cell subset with important regulatory functions, which are thought to result essentially from their capacity to promptly produce cytokines that influence the Th1/Th2 balance. In this study, we report that these cells can also express Foxp3, an important transcriptional regulator associated with suppressive activity, once they have been exposed to TGF-β. Foxp3 was expressed by iNKT cells from both peripheral and cord blood. CD4(+) iNKT cells acquired Foxp3 expression preferentially, although a lower proportion of their CD4(-) counterpart also became positive. All Foxp3(+) iNKT cells displayed CD25 but not necessarily CTLA4 or GITR, regardless of the upregulation of these markers in the presence of TGF-β. Exposure to TGF-β decreased IL-4 and IFN-γ production while increasing IL-10, independently from Foxp3 expression. IL-17 was not detected. TGF-β induced high levels of Foxp3, but no suppressor activity, which emerged only in the presence of rapamycin. Peripheral and cord blood Foxp3(+) iNKT cells suppressed the proliferation of conventional autologous and heterologous CD4(+) T cells equally, in a cell contact-dependent and Ag-independent manner. Our findings demonstrate that human iNKT cells become suppressive in the presence of TGF-β plus rapamycin, thus adding a new facet to their complex functional properties.
authors.affiliation: Unité Mixte de Recherche 8147, Centre National de la Recherche Scientifique, Faculté de Médecine René Descartes, Paris V, Hôpital Necker, 75015 Paris, France.
authors.forename: Lúcia
authors.initials: L
authors.lastname: Moreira-Teixeira
authors.forename: Mariana
authors.initials: M
authors.lastname: Resende
authors.forename: Odile
authors.initials: O
authors.lastname: Devergne
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Herbeuval
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.forename: Elke
authors.initials: E
authors.lastname: Schneider
authors.forename: Michel
authors.initials: M
authors.lastname: Dy
authors.forename: Anabela
authors.initials: A
authors.lastname: Cordeiro-da-Silva
authors.forename: Maria C
authors.initials: MC
authors.lastname: Leite-de-Moraes
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005312:Fetal Blood / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D055611:Natural Killer T-Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D020123:Sirolimus / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007166:Immunosuppressive Agents; D016212:Transforming Growth Factor beta; D020123:Sirolimus