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

Yue Li, Xiaoqun Guan, Weiren Liu, Hung Lin Chen, Sonay Beyatli, Ahmed Metwali, George J. Weiner, Nicholas Zavazava, Richard S. Blumberg, Joseph F. Urban, Bruce R Blazar, David E. Elliott, M. Nedim Ince

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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-b and is associated with TGF-b-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-b-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-b secretion, TGF-b-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-b. In contrast, TGF-b is not necessary for GATA3 expression by Foxp3+ Tregs or by Foxp32 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-b 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. The Journal of Immunology, 2018, 201: 2910-2922.

Original languageEnglish (US)
Pages (from-to)2910-2922
Number of pages13
JournalJournal of Immunology
Volume201
Issue number10
DOIs
StatePublished - Nov 15 2018

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

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