Heligmosomoides polygyrus bakeri Infection Decreases Smad7 Expression in Intestinal CD4+ T Cells, Which Allows TGF-β to Induce IL-10-Producing Regulatory T Cells That Block Colitis.
Long HangSangeeta KumarArthur M BlumJoseph F UrbanMassimo C FantiniJoel V WeinstockPublished in: Journal of immunology (Baltimore, Md. : 1950) (2019)
Helminthic infections modulate host immunity and may protect their hosts from developing immunological diseases like inflammatory bowel disease. Induction of regulatory T cells (Tregs) may be an important part of this protective process. Heligmosomoides polygyrus bakeri infection also promotes the production of the regulatory cytokines TGF-β and IL-10 in the gut. In the intestines, TGF-β helps induce regulatory T cells. This study used Foxp3/IL-10 double reporter mice to investigate the effect of TGF-β on the differentiation of colon and mesenteric lymph node-derived murine Foxp3- IL-10- CD4+ T cells into their regulatory phenotypes. Foxp3- IL-10- CD4+ T cells from H. polygyrus bakeri-infected mice, as opposed to T cells from uninfected animals, cultured in vitro with TGF-β and anti-CD3/CD28 mAb differentiated into Foxp3+ and/or IL-10+ T cells. The IL-10-producing T cells nearly all displayed CD25. Smad7 is a natural inhibitor of TGF-β signaling. In contrast to gut T cells from uninfected mice, Foxp3- IL10- CD4+ T cells from H. polygyrus bakeri-infected mice displayed reduced Smad7 expression and responded to TGF-β with Smad2/3 phosphorylation. The TGF-β-induced Tregs that express IL-10 blocked colitis when transferred into the Rag/CD25- CD4+ T cell transfer model of inflammatory bowel disease. TGF-β had a greatly diminished capacity to induce Tregs in H. polygyrus bakeri-infected transgenic mice with constitutively high T cell-specific Smad7 expression. Thus, infection with H. polygyrus bakeri causes down-modulation in Smad7 expression in intestinal CD4+ T cells, which allows the TGF-β produced in response to the infection to induce the Tregs that prevent colitis.
Keyphrases
- regulatory t cells
- transforming growth factor
- epithelial mesenchymal transition
- dendritic cells
- poor prognosis
- lymph node
- magnetic resonance
- radiation therapy
- squamous cell carcinoma
- binding protein
- type diabetes
- immune response
- ulcerative colitis
- hiv infected
- nk cells
- monoclonal antibody
- wild type
- antiretroviral therapy