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

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

doi:10.4049/jimmunol.1700638

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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

Journal article

Peer reviewed

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

Xiaoqun Guan, Yue Li, Ahmed Metwali, George J Weiner, Weiren Liu, Nicholas Zavazava, Hung-Lin Chen, David E Elliott, Jamie Truscott, M Nedim Ince, …

The Journal of immunology (1950), Vol.201(10), pp.2910-2922

11/15/2018

DOI: 10.4049/jimmunol.1700638

PMCID: PMC6219912

PMID: 30291167

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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-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.

Bone Marrow Transplantation

Transforming Growth Factor beta - immunology

GATA3 Transcription Factor - immunology

Mice, Inbred C57BL

Male

Graft vs Host Disease - immunology

Transforming Growth Factor beta - biosynthesis

T-Lymphocytes, Regulatory - immunology

CD4-Positive T-Lymphocytes - immunology

Interleukin-4 - immunology

Interleukin-4 - biosynthesis

Lymphocyte Activation - immunology

Animals

Nematospiroides dubius

Strongylida Infections - immunology

Mice

Mice, Inbred BALB C

GATA3 Transcription Factor - metabolism

Details

Title: Subtitle: Helminth-Induced Production of TGF-β and Suppression of Graft-versus-Host Disease Is Dependent on IL-4 Production by Host Cells
Creators: Xiaoqun Guan - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
Yue Li - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
Ahmed Metwali - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
George J Weiner - Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
Weiren Liu - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
Nicholas Zavazava - Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
Hung-Lin Chen - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
David E Elliott - Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
Jamie Truscott - Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
M Nedim Ince - Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
Sonay Beyatli - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
Richard S Blumberg - Department of Internal Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115
Joseph F Urban Jr - Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, MD 20705; and
Bruce R Blazar - Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455
Resource Type: Journal article
Publication Details: The Journal of immunology (1950), Vol.201(10), pp.2910-2922
DOI: 10.4049/jimmunol.1700638
PMID: 30291167
PMCID: PMC6219912
NLM abbreviation: J Immunol
ISSN: 0022-1767
eISSN: 1550-6606
Grant note: R01 AI034495 / NIAID NIH HHS P30 ES005605 / NIEHS NIH HHS R56 AI116715 / NIAID NIH HHS R01 HL095791 / NHLBI NIH HHS I01 BX002906 / BLRD VA R01 HL118979 / NHLBI NIH HHS I01 BX002715 / BLRD VA U19 AI051731 / NIAID NIH HHS P30 CA086862 / NCI NIH HHS R37 AI034495 / NIAID NIH HHS R37 HL056067 / NHLBI NIH HHS R01 DK044319 / NIDDK NIH HHS R01 HL056067 / NHLBI NIH HHS
Language: English
Date published: 11/15/2018
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Hematology, Oncology, and Blood & Marrow Transplantation; Gastroenterology and Hepatology; Pharmaceutical Sciences and Experimental Therapeutics; Radiation Oncology; Internal Medicine
Record Identifier: 9984094535802771

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