Induced CD4+ forkhead box protein-positive T cells inhibit mast cell function and established contact hypersensitivity through TGF-β1.
BACKGROUND
Induced CD4(+) forkhead box protein 3-positive regulatory T (iTreg) cells are a promising source for cell-based therapies of established inflammatory and autoimmune diseases. However, their relationship to mast cell (MC) function and MC-driven diseases remains unknown.


OBJECTIVE
We sought to explore the roles of iTreg cells on MC function and the established MC-driven disease contact hypersensitivity (CHS).


METHODS
In vitro coculture studies were carried out to investigate the interaction between iTreg cells in murine or human MCs by using both direct cell-cell contact and transwell systems to separate cell-cell contact. In vivo mice iTreg cells were administered to mice with established CHS, and innate immunologic responses, such as MC infiltration and inflammatory cytokine expression at contact sites, were evaluated.


RESULTS
In vitro coculture under direct cell-cell contact resulted in indirect suppression of IgE-independent activation of MCs by murine or human iTreg cells. Mechanistically, iTreg cells suppressed proinflammatory cytokine levels by modulating nuclear factor κB p65 activation in MCs through T cell-derived TGF-β1. Injection of iTreg cells but not natural CD4(+)CD25(+) regulatory T cells into animals with established CHS resulted in the suppression of infiltration and functions of MCs and also led to decreased production of inflammatory cytokines at allergic contact areas. iTreg cell-mediated immunosuppressive effects were abrogated when iTreg cells were pretreated with TGF-β1 small interfering RNA.


CONCLUSIONS
Our study demonstrates that iTreg cells suppress MC function and attenuate established MC-driven CHS through TGF-β1-dependent mechanisms.
Division of Rheumatology and Immunology, Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA90033, USA.
Wenru
W
Su
Huimin
H
Fan
Maogen
M
Chen
Julie
J
Wang
David
D
Brand
Xiaoshun
X
He
Valerie
V
Quesniaux
Bernhard
B
Ryffel
Ling
L
Zhu
Dan
D
Liang
Song Guo
SG
Zheng
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D018920:Coculture Techniques; D003877:Dermatitis, Contact / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D015194:Diffusion Chambers, Culture; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D017710:Lymphocyte Transfusion; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D034741:RNA, Small Interfering / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000276:immunology
D015703:Antigens, CD; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D016328:NF-kappa B; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1