Abstract
Immune homeostasis in the intestine is tightly controlled by FOXP3+ regulatory T cells (Tregs), defects of which are linked to the 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) that mimics the ability of TGF‐β to induce FOXP3 expression in CD4+ T cells. The study 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 with 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.
Highlights
Heligmosomoides polygyrus is a parasitic nematode of mice that establishes long-term infections in the intestinal tract and releases a diverse array of excretory/secretory products (HES), which promotes parasite survival
Analysis of the dose titration results obtained from all donors, and in experiments that used anti-CD3/CD28 bead stimulation (Supplementary figure 1 and data not shown), led us to select 100 ng mLÀ1 Hp-TGM as the concentration that most consistently induced maximal FOXP3 expression and this concentration was used for the remainder of the study
We show here that a novel parasite-derived TGF-b mimic protein (Hp-TGM) is able to induce FOXP3+ Tregs from both na€ıve and memory human CD4+ T cells in vitro
Summary
Heligmosomoides polygyrus is a parasitic nematode of mice that establishes long-term infections in the intestinal tract and releases a diverse array of excretory/secretory products (HES), which promotes parasite survival. A TGF-b-mimic induces human FOXP3+ Tregs inflammatory pathways and promote immunosuppressive cell populations.[2,3] For example, HES contains molecules that block the cytokine IL-33 and its receptor ST2,4,5 impair dendritic cell function[6] and suppress macrophages.[7] Recently, another HES protein was identified as a TGF-b mimic, termed Hp-TGM (H. polygyrus TGF-b mimic), which, despite the lack of sequence homology, triggered mammalian TGF-b signaling pathways through binding TGF-b receptors.[8]. Hp-TGM induced FOXP3 expression in both mouse and human CD4+ T cells, with mouse induced FOXP3+ regulatory T cells (Tregs) shown to have suppressive function both in vitro[8] and in vivo.[9]. FOXP3+ Tregs have a key role in maintaining selftolerance and immune homeostasis and in vivo are generated in both the thymus and the periphery.[10]
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