Article: Helminth-Induced Production of TGF-β and Suppression of Graft-versus-Host Disease Is Dependent on IL-4 Production by Host Cells
Authors: Yue Li, Xiaoqun Guan, Weiren Liu, Hung-Lin Chen, Jamie Truscott, Sonay Beyatli, Ahmed Metwali, George J. Weiner, Nicholas Zavazava, Richard S. Blumberg, Joseph F. Urban Jr., Bruce R. Blazar, David E. Elliott and M. Nedim Ince
Journal: J Immunol. 2018 Oct 5. pii: ji1700638. doi: 10.4049/jimmunol.1700638. [Epub ahead of print]
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+ 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 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-β secretion, TGF-β-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-β. In contrast, TGF-β 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-β 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.
Link to journal online: http://www.jimmunol.org/content/early/2018/10/04/jimmunol.1700638.long