Induction of stable human FOXP3 + Tregs by a parasite‐derived TGF‐β mimic

Cook, L. et al. (2021) Induction of stable human FOXP3 + Tregs by a parasite‐derived TGF‐β mimic. Immunology and Cell Biology, 99(8), pp. 833-847. (doi: 10.1111/imcb.12475) (PMID:33929751)

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Abstract

Immune homeostasis in the intestine is tightly controlled by FOXP3+ regulatory T cells (Tregs), defects in which are linked to development of chronic conditions, such as inflammatory bowel disease (IBD). As a mechanism of immune evasion, several species of intestinal parasites boost Treg activity. The parasite Heligmosomoides polygyrus is known to secrete a molecule (Hp-TGM) which mimics the ability of TGF-β to induce FOXP3 expression in CD4+ T cells. We aimed to investigate whether Hp-TGM could induce human FOXP3+ Tregs as a potential therapeutic approach for inflammatory diseases. CD4+ T cells from healthy volunteers were expanded in the presence of Hp-TGM or TGF-β. Treg induction was measured by flow cytometric detection of FOXP3 and other Treg markers, such as CD25 and CTLA-4. Epigenetic changes were detected using ChIP-Seq and pyrosequencing of FOXP3. Treg phenotype stability was assessed following inflammatory cytokine challenge and Treg function was evaluated by cellular co-culture suppression assays and cytometric bead arrays for secreted cytokines. Hp-TGM efficiently induced FOXP3 expression (> 60%), in addition to CD25 and CTLA-4, and caused epigenetic modification of the FOXP3 locus to a greater extent than TGF-β. Hp-TGM-induced Tregs had superior suppressive function compared to TGF-β-induced Tregs, and retained their phenotype following exposure to inflammatory cytokines. Furthermore, Hp-TGM induced a Treg-like phenotype in in vivo differentiated Th1 and Th17 cells, indicating its potential to re-program memory cells to enhance immune tolerance. These data indicate Hp-TGM has potential to be used to generate stable human FOXP3+ Tregs to treat IBD and other inflammatory diseases.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:White, Dr Madeleine and Maizels, Professor Rick and Smyth, Dr Danielle
Authors: Cook, L., Reid, K. T., Häkkinen, E., de Bie, B., Tanaka, S., Smyth, D. J., White, M. P.J., Wong, M. Q., Huang, Q., Gillies, J. K., Zeigler, S. F., Maizels, R. M., and Levings, M. K.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Research Centre:College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
Journal Name:Immunology and Cell Biology
Publisher:Wiley
ISSN:0818-9641
ISSN (Online):1440-1711
Published Online:30 April 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Immunology and Cell Biology 99(8): 833-847
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/ZSchool of Infection & Immunity
170547The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOTR)104111/Z/14/ZSII - Parasitology