期刊
JOURNAL OF IMMUNOLOGY
卷 201, 期 10, 页码 2910-2922出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1700638
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资金
- National Institutes of Health [R56 AI 116715, R01 HL56067, AI34495, HL11879, DK443119]
- Department of Veterans Affairs [BX002906, BX002715]
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-beta and is associated with TGF-beta-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-beta-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-beta secretion, TGF-beta-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-beta. In contrast, TGF-beta 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-beta 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.
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