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Helminth-Induced Production of TGF-? and Suppression of Graft-versus-Host Disease Is Dependent on IL-4 Production by Host Cells.


ABSTRACT: Helminths stimulate the secretion of Th2 cytokines, like IL-4, and suppress lethal graft-versus-host disease (GVHD) after bone marrow transplantation. This suppression depends on the production of immune-modulatory TGF-? and is associated with TGF-?-dependent in vivo expansion of Foxp3+ regulatory T cells (Treg). In vivo expansion of Tregs is under investigation for its potential as a therapy for GVHD. Nonetheless, the mechanism of induced and TGF-?-dependent in vivo expansion of Tregs, in a Th2 polarized environment after helminth infection, is unknown. In this study, we show that helminth-induced IL-4 production by host cells is critical to the induction and maintenance of TGF-? secretion, TGF-?-dependent expansion of Foxp3+ Tregs, and the suppression of GVHD. In mice with GVHD, the expanding donor Tregs express the Th2-driving transcription factor, GATA3, which is required for helminth-induced production of IL-4 and TGF-?. In contrast, TGF-? is not necessary for GATA3 expression by Foxp3+ Tregs or by Foxp3- CD4 T cells. Various cell types of innate or adaptive immune compartments produce high quantities of IL-4 after helminth infection. As a result, IL-4-mediated suppression of GVHD does not require invariant NKT cells of the host, a cell type known to produce IL-4 and suppress GVHD in other models. Thus, TGF-? generation, in a manner dependent on IL-4 secretion by host cells and GATA3 expression, constitutes a critical effector arm of helminthic immune modulation that promotes the in vivo expansion of Tregs and suppresses GVHD.

SUBMITTER: Li Y 

PROVIDER: S-EPMC6219912 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Helminth-Induced Production of TGF-β and Suppression of Graft-versus-Host Disease Is Dependent on IL-4 Production by Host Cells.

Li Yue Y   Guan Xiaoqun X   Liu Weiren W   Chen Hung-Lin HL   Truscott Jamie J   Beyatli Sonay S   Metwali Ahmed A   Weiner George J GJ   Zavazava Nicholas N   Blumberg Richard S RS   Urban Joseph F JF   Blazar Bruce R BR   Elliott David E DE   Ince M Nedim MN  

Journal of immunology (Baltimore, Md. : 1950) 20181005 10


Helminths stimulate the secretion of Th2 cytokines, like IL-4, and suppress lethal graft-versus-host disease (GVHD) after bone marrow transplantation. This suppression depends on the production of immune-modulatory TGF-β and is associated with TGF-β-dependent in vivo expansion of Foxp3<sup>+</sup> regulatory T cells (Treg). In vivo expansion of Tregs is under investigation for its potential as a therapy for GVHD. Nonetheless, the mechanism of induced and TGF-β-dependent in vivo expansion of Treg  ...[more]

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