title: FoxP3+RORgammat+ T helper intermediates display suppressive function against autoimmune diabetes.
abstract: Recently, traces of double-positive FoxP3(+)RORgammat(+) T cells were identified and viewed as dual programming differentiation intermediates geared toward development into T regulatory or Th17 cells. In this study, we report that FoxP3(+)RORgammat(+) intermediates arise in the NOD mouse T cell repertoire prior to inflammation and can be expanded with tolerogen without further differentiation. Furthermore, FoxP3(+)RORgammat(+) cells express both CD62L and membrane-bound TGFbeta and use the former to traffic to the pancreas and the latter to suppress effector T cells both in vitro and in vivo. The cells perform these functions as FoxP3(+)RORgammat(+) intermediates, despite being able to terminally differentiate into either FoxP3(+)RORgammat(-) T regulatory or FoxP3(-)RORgammat(+) Th17 cells on polarization. These previously unrecognized observations extend plasticity to both differentiation and function and indicate that the intermediates are poised to traffic to sites of inflammation and target diverse pathogenic T cells, likely without prior conditioning by effector T cells, thus broadening efficacy against autoimmunity.
authors.affiliation: Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO 65212, USA.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Tartar
authors.forename: Amie M
authors.initials: AM
authors.lastname: VanMorlan
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Wan
authors.forename: F Betul
authors.initials: FB
authors.lastname: Guloglu
authors.forename: Renu
authors.initials: R
authors.lastname: Jain
authors.forename: Cara L
authors.initials: CL
authors.lastname: Haymaker
authors.forename: Jason S
authors.initials: JS
authors.lastname: Ellis
authors.forename: Christine M
authors.initials: CM
authors.lastname: Hoeman
authors.forename: Jason A
authors.initials: JA
authors.lastname: Cascio
authors.forename: Mermagya
authors.initials: M
authors.lastname: Dhakal
authors.forename: Mohamed
authors.initials: M
authors.lastname: Oukka
authors.forename: Habib
authors.initials: H
authors.lastname: Zaghouani
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002469:Cell Separation; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology* / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3