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 |
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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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