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

Madeleine P. J. White, Danielle J. Smyth, Laura Cook, Steven F. Ziegler, Megan K. Levings, Rick M. Maizels (Lead / Corresponding author)

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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 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.

Original languageEnglish
Number of pages37
JournalImmunology and Cell Biology
Early online date14 May 2021
DOIs
Publication statusE-pub ahead of print - 14 May 2021

Keywords

  • autoimmunity
  • immune evasion
  • parasite cytokines
  • regulatory T cells

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