TY - JOUR
T1 - The parasite cytokine mimic Hp-TGM potently replicates the regulatory effects of TGF-β on murine CD4+ T cells
AU - White, Madeleine P. J.
AU - Smyth, Danielle J.
AU - Cook, Laura
AU - Ziegler, Steven F.
AU - Levings, Megan K.
AU - Maizels, Rick M.
N1 - Funding Information:
We thank Nicola Britton and Claire Ciancia for excellent technical assistance. The authors gratefully acknowledge the Flow Core Facility, University of Glasgow for their support and assistance as well as BD Biosciences for their panel design expertise. We thank Jana Gillies for her help in running and designing the mouse TSDR assay, and Andy Hinck for his critical comments on the manuscript. This work was supported by the Kenneth Rainin Foundation through Synergy and Innovator Grants (Refs 2015‐964 and 2016‐3067), the Wellcome Trust through an Investigator Award to RMM (Ref 106122), the Wellcome Trust core‐funded Wellcome Centre for Integrative Parasitology (Ref: 104111) and by the Medical Research Council Confidence‐in‐Concept scheme. MKL and LC received salary awards from the BC Children’s Hospital Research Institute.
Publisher Copyright:
© 2021 The Authors. Immunology & Cell Biology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.
PY - 2021/9
Y1 - 2021/9
N2 - 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 interleukin-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 with 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 programmed death-ligand 1, but Hp-TGM induced significantly higher CD39 expression than did TGF-β. Interestingly, in contrast to canonical TGF-β signaling 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 experimental autoimmune encephalomyelitis-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 dextran sodium sulfate-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.
AB - 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 interleukin-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 with 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 programmed death-ligand 1, but Hp-TGM induced significantly higher CD39 expression than did TGF-β. Interestingly, in contrast to canonical TGF-β signaling 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 experimental autoimmune encephalomyelitis-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 dextran sodium sulfate-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.
KW - autoimmunity
KW - immune evasion
KW - parasite cytokines
KW - regulatory T cells
UR - http://www.scopus.com/inward/record.url?scp=85107078380&partnerID=8YFLogxK
U2 - 10.1111/imcb.12479
DO - 10.1111/imcb.12479
M3 - Article
C2 - 33988885
SN - 0818-9641
VL - 99
SP - 848
EP - 864
JO - Immunology and Cell Biology
JF - Immunology and Cell Biology
IS - 8
ER -