Abstract
We recently reported the discovery of a new parasite-derived protein that functionally mimics the immunosuppressive cytokine transforming growth factor (TGF)-β. The Heligmosomoides polygyrus TGF-β Mimic (Hp-TGM) shares no homology to any TGF-β family member, however it binds the mammalian TGF-β receptor and induces expression of Foxp3, the canonical transcription factor of both mouse and human regulatory T cells. Hp-TGM consists of five atypical Complement Control Protein (CCP, Pfam 00084) domains, each lacking certain conserved residues and 12–15 amino acids longer than the 60–70 amino acids consensus domain, but with a recognizable 3-cysteine, tryptophan, cysteine motif. We now report on the identification of a family of nine related Hp-TGM homologues represented in the secreted proteome and transcriptome of H. polygyrus. Recombinant proteins from five of the nine new TGM members were tested for TGF-β activity, but only two were functionally active in an MFB-F11 reporter assay, and by the induction of T cell Foxp3 expression. Sequence comparisons reveal that proteins with functional activity are similar or identical to Hp-TGM across the first three CCP domains, but more variable in domains 4 and 5. Inactive proteins diverged in all domains, or lacked some domains entirely. Testing truncated versions of Hp-TGM confirmed that domains 1–3 are essential for full activity in vitro, while domains 4 and 5 are not required. Further studies will elucidate whether these latter domains fulfill other functions in promoting host immune regulation during infection and if the more divergent family members play other roles in immunomodulation.
Highlights
Helminth parasites are well-recognised for their wide-ranging immunomodulatory properties, which in many instances are linked to the stimulation of regulatory T cells (Tregs) that dampen immunity and inflammation (McSorley and Maizels, 2012; Finlay et al, 2014)
2016), and mechanistically we showed that parasite secretion of a transforming growth factor (TGF)-b-like protein can account for its ability to expand Treg populations in vivo (Grainger et al, 2010)
Smyth et al / International Journal for Parasitology 48 (2018) 379–385 et al, 2016), and vice versa (Beall and Pearce, 2001; ZavalaGongora et al, 2006). Despite this evidence for inter-phylum cross-talk between homologous ligands and receptors, and the identification of the TGF-b homologues encoded by H. polygyrus (McSorley et al, 2010), we recently reported that the ability of this parasite to activate the TGF-b pathway resides not with a true homologue, but a structurally novel mimic which replicates the functional activity of this immunosuppressive cytokine (Johnston et al, 2017)
Summary
Helminth parasites are well-recognised for their wide-ranging immunomodulatory properties, which in many instances are linked to the stimulation of regulatory T cells (Tregs) that dampen immunity and inflammation (McSorley and Maizels, 2012; Finlay et al, 2014). The murine intestinal helminth Heligmosomoides polygyrus is linked to suppression via Tregs
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