FoxP3+RORgammat+ T helper intermediates display suppressive function against autoimmune diabetes.
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.
Tartar
Danielle M
DM
Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO 65212, USA.
VanMorlan
Amie M
AM
Wan
Xiaoxiao
X
Guloglu
F Betul
FB
Jain
Renu
R
Haymaker
Cara L
CL
Ellis
Jason S
JS
Hoeman
Christine M
CM
Cascio
Jason A
JA
Dhakal
Mermagya
M
Oukka
Mohamed
M
Zaghouani
Habib
H
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
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3