The parasite cytokine mimic Hp-TGM potently replicates the regulatory effects of TGF-β on murine CD4+ T cells

White, M. P.J., Smyth, D. J. , Cook, L., Ziegler, S. F., Levings, M. K. and Maizels, R. M. (2021) The parasite cytokine mimic Hp-TGM potently replicates the regulatory effects of TGF-β on murine CD4+ T cells. Immunology and Cell Biology, 99(8), pp. 848-864. (doi: 10.1111/imcb.12479) (PMID:33988885) (PMCID:PMC9214624)

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Abstract

Transforming growth factor‐beta (TGF‐β) family proteins mediate many vital biological functions in growth, development and regulation of the immune system. TGF‐β itself controls immune homeostasis and inflammation, including conversion of naïve CD4+ T cells into Foxp3+ regulatory T cells (Tregs) in the presence of IL‐2 and T cell receptor ligands. The helminth parasite Heligmosomoides polygyrus exploits this pathway through a structurally novel TGF‐β mimic (Hp‐TGM), which binds to mammalian TGF‐β receptors and induces Tregs. Here, we performed detailed comparisons of Hp‐TGM with mammalian TGF‐β. Compared to TGF‐β, Hp‐TGM induced greater numbers of Foxp3+ Tregs (iTregs), with more intense Foxp3 expression. Both ligands upregulated Treg functional markers CD73, CD103 and PD‐L1, but Hp‐TGM induced significantly higher CD39 expression than did TGF‐β. Interestingly, in contrast to canonical TGF‐β signalling through Smad2/3, Hp‐TGM stimulation was slower and more sustained. Gene expression profiles induced by TGF‐β and Hp‐TGM were remarkably similar, and both types of iTregs suppressed T cell responses in vitro and EAE‐driven inflammation in vivo. In vitro, both types of iTregs were equally stable under inflammatory conditions, but Hp‐TGM‐induced iTregs were more stable in vivo during DSS‐induced colitis, with greater retention of Foxp3 expression and lower conversion to a ROR‐γt+ phenotype. Altogether, results from this study suggest that the parasite cytokine mimic, Hp‐TGM, may deliver a qualitatively different signal to CD4+ T cells with downstream consequences for the long‐term stability of iTregs. These data highlight the potential of Hp‐TGM as a new modulator of T cell responses in vitro and in vivo.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:White, Dr Madeleine and Maizels, Professor Rick and Smyth, Dr Danielle
Creator Roles:
White, M. P.J.Conceptualization, Investigation, Methodology, Writing – original draft
Smyth, D. J.Investigation, Methodology
Maizels, R. M.Conceptualization, Data curation, Formal analysis, Funding acquisition, Project administration, Supervision, Writing – original draft, Writing – review and editing
Authors: White, M. P.J., Smyth, D. J., Cook, L., Ziegler, S. F., Levings, M. K., and Maizels, R. M.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Immunology and Cell Biology
Publisher:Wiley
ISSN:0818-9641
ISSN (Online):1440-1711
Published Online:14 May 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Immunology and Cell Biology 99(8): 848-864
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
173801Helminths and the Immune System: Regulation, Regulators and ImmunityRichard MaizelsWellcome Trust (WELLCOTR)106122/A/14/ZInstitute of Infection, Immunity & Inflammation
170547The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOTR)104111/Z/14/ZRIII - Parasitology