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 language | English (US) |
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Pages (from-to) | 2910-2922 |
Number of pages | 13 |
Journal | Journal of Immunology |
Volume | 201 |
Issue number | 10 |
DOIs | |
State | Published - Nov 15 2018 |
Bibliographical note
Funding Information:This work was supported by research funds from the National Institutes of Health: R56 AI 116715 (to M.N.I.), R01 HL56067, AI34495, HL11879 (to B.R.B.), and
Publisher Copyright:
Copyright © 2018 by The American Association of Immunologists, Inc. All rights reserved
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, U.S. Gov't, Non-P.H.S.