title: IL4 blockade of inducible regulatory T cell differentiation: the role of Th2 cells, Gata3 and PU.1.
abstract: Naive CD4 T cells differentiate into functionally distinct T helper (Th) cells subsets or into regulatory T (Treg) cells in response to the cytokine milieu in which they encounter antigen. A recurring theme in post-thymic CD4 T cell differentiation is the cross-regulation of lineage choice by cytokines and transcription factors that are expressed in alternative lineages. For example, TGFbeta induces the de novo expression of the Treg cell signature transcription factor Foxp3, but iTreg differentiation is blocked by high concentrations of the Th2 cytokine IL4. However, whether IL4 can antagonise Foxp3 induction in more physiological settings remains to be addressed. Here we use a co-culture system to demonstrate that IL4 provided by Th2 cells in vitro is sufficient to block Foxp3 induction in naive CD4 T cells. In addition, we find that Foxp3 induction is efficiently blocked not only by the Th2 transcription factor Gata3, but also by PU.1, which is transiently induced during Th2 differentiation. These data suggest that iTreg differentiation may be affected by the polarity of immune responses.
authors.affiliation: Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College London, Du Cane Road, London W12 0NN, UK.
authors.forename: Suzana
authors.initials: S
authors.lastname: Hadjur
authors.forename: Ludovica
authors.initials: L
authors.lastname: Bruno
authors.forename: Arnulf
authors.initials: A
authors.lastname: Hertweck
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Cobb
authors.forename: Benjamin
authors.initials: B
authors.lastname: Taylor
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Fisher
authors.forename: Matthias
authors.initials: M
authors.lastname: Merkenschlager
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D018920:Coculture Techniques; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D050800:STAT6 Transcription Factor / Q000172:deficiency; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015533:Transcriptional Activation / Q000276:immunology; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D051858:Forkhead Transcription Factors; D050990:GATA3 Transcription Factor; D015847:Interleukin-4; D011518:Proto-Oncogene Proteins; D050800:STAT6 Transcription Factor; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C498833:Foxp3 protein, mouse; C494748:Gata3 protein, mouse; C494100:Stat6 protein, mouse