title: Helios is associated with CD4 T cells differentiating to T helper 2 and follicular helper T cells in vivo independently of Foxp3 expression.
abstract: BACKGROUND
  Although in vitro IL-4 directs CD4 T cells to produce T helper 2 (Th2)-cytokines, these cytokines can be induced in vivo in the absence of IL-4-signalling. Thus, mechanism(s), different from the in vitro pathway for Th2-induction, contribute to in vivo Th2-differentiation. The pathway for in vivo IL-4-independent Th2-differentiation has yet to be characterized.
  
  
  RESULTS
  Helios (ikzf2), a member of the Ikaros transcription regulator family, is expressed in thymocytes and some antigen-matured T cells as well as in regulatory T cells. It has been proposed that Helios is a specific marker for thymus-derived regulatory T cells. Here, we show that mouse ovalbumin-specific CD4 (OTII) cells responding to alum-precipitated ovalbumin (alumOVA) upregulate Th2 features - GATA-3 and IL-4 - as well as Helios mRNA and protein. Helios is also upregulated in follicular helper T (TFh) cells in this response. By contrast, OTII cells responding to the Th1 antigen - live attenuated ovalbumin-expressing Salmonella - upregulate Th1 features - T-bet and IFN-γ - but not Helios. In addition, CD4 T cells induced to produce Th2 cytokines in vitro do not express Helios. The kinetics of Helios mRNA and protein induction mirrors that of GATA-3. The induction of IL-4, IL-13 and CXCR5 by alumOVA requires NF-κB1 and this is also needed for Helios upregulation. Importantly, Helios is induced in Th2 and TFh cells without parallel upregulation of Foxp3. These findings suggested a key role for Helios in Th2 and TFh development in response to alum-protein vaccines. We tested this possibility using Helios-deficient OTII cells and found this deficiency had no discernable impact on Th2 and TFh differentiation in response to alumOVA.
  
  
  CONCLUSIONS
  Helios is selectively upregulated in CD4 T cells during Th2 and TFh responses to alum-protein vaccines in vivo, but the functional significance of this upregulation remains uncertain.
authors.affiliation: School of Immunity and Infection, MRC Centre for Immune Regulation, Institute for Biomedical Research, University of Birmingham, Birmingham, England, United Kingdom.
authors.forename: Karine
authors.initials: K
authors.lastname: Serre
authors.forename: Cécile
authors.initials: C
authors.lastname: Bénézech
authors.forename: Guillaume
authors.initials: G
authors.lastname: Desanti
authors.forename: Saeeda
authors.initials: S
authors.lastname: Bobat
authors.forename: Kai-Michael
authors.initials: KM
authors.lastname: Toellner
authors.forename: Roger
authors.initials: R
authors.lastname: Bird
authors.forename: Susan
authors.initials: S
authors.lastname: Chan
authors.forename: Philippe
authors.initials: P
authors.lastname: Kastner
authors.forename: Adam F
authors.initials: AF
authors.lastname: Cunningham
authors.forename: Ian C M
authors.initials: IC
authors.lastname: Maclennan
authors.forename: Elodie
authors.initials: E
authors.lastname: Mohr
mesh_terms: D019264:Adoptive Transfer; D000534:Alum Compounds / Q000494:pharmacology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D002460:Cell Line / Q000187:drug effects; D016207:Cytokines / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology*; D050990:GATA3 Transcription Factor / Q000378:metabolism; D018793:Interleukin-13 / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology*; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology*
chemical_list: D000534:Alum Compounds; D016207:Cytokines; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D018793:Interleukin-13; D016328:NF-kappa B; D014157:Transcription Factors; C491746:Zfpn1a2 protein, mouse; C446402:ovalbumin-alum; D015847:Interleukin-4; D010047:Ovalbumin