Skip to main content
ARS Home » Northeast Area » Beltsville, Maryland (BHNRC) » Beltsville Human Nutrition Research Center » Diet, Genomics and Immunology Laboratory » Research » Publications at this Location » Publication #346998
Title: Heligmosomoides polygyrus bakeri infection decreases Smad7 expression in intestinal CD4+ T cells which allows TGF-beta to induce IL10-producing regulatory T cells that block colitis

Author
item HANG, LONG - Tufts - New England Medical Center
item KUMAR, SANGEETA - Tufts - New England Medical Center
item BLUM, ARTHUR - Tufts - New England Medical Center
item Urban, Joseph
item FANTINI, M - Tufts - New England Medical Center
item WEINSTOCK, JOEL - Tufts - New England Medical Center

Submitted to: Journal of Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/8/2019
Publication Date: 4/15/2019
Citation: Hang, L., Kumar, S., Blum, A.M., Urban Jr, J.F., Fantini, M.X., Weinstock, J.V. 2019. Heligmosomoides polygyrus bakeri infection decreases Smad7 expression in intestinal CD4+ T cells which allows TGF-beta to induce IL10-producing regulatory T cells that block colitis. Journal of Immunology. (8)2473-2481. https://doi.org/10.4049/jimmunol.1801392.
DOI: https://doi.org/10.4049/jimmunol.1801392

Interpretive Summary: People from worm infected areas of the world have been observed to have reduced expression of Inflammatory Bowel Disease (IBD); which has led to the hypothesis that parasitic worms can reduce inflammation in humans. This hypothesis has been tested in a mouse model that isolates special regulatory cells from the tissues of the intestinal colon after infection with worms and transfers them to other mice that have IBD. Scientists from the Tufts University Medical Center and USDA/ARS in Beltsville showed that these transferred cells were able to reduce the intensity of IBD. It appears that the worm infection blocks the production of an intracellular signaling molecule that, in turn, facilitates the production of certain anti-inflammatory proteins that are secreted by the cells from the gut to reduce inflammation. Blockage of this intracellular molecule (SMAD7) in people with IBD has shown some limited clinical success. This information is important to researchers that want to understand how parasite modulate responses in the intestine and how these response can be regulated to reduce disease.

Technical Abstract: Helminthic infections modulate host immunity and may protect their hosts from developing immunological diseases like inflammatory bowel disease (IBD). Induction of T regulatory cells (Tregs) may be an important part of this protective process. Transferring colonic Tregs from mice with Heligmosomoides polygyrus bakeri (Hpb) infection into murine models of colitis can prevent the disease, while colonic Tregs for uninfected mice fail to provide protection. Hpb infection also promotes the production of the regulatory cytokines TGF-beta and IL10 in the gut. This study, using Foxp3/IL10 double reporter mice, investigated the effect of TGF-beta on the differentiation of colon and MLN-derived, murine Foxp3-IL10-CD4+ T cells into their regulatory phenotypes. Foxp3-IL10-CD4+ T cells from Hpb-infected mice, as opposed to T cells from uninfected animals, cultured in vitro with TGF-beta and anti-CD3/CD28 monoclonal antibody differentiated into Foxp3+ and/or IL10+ T cells. The IL10 producing T cells nearly all displayed CD25. Smad7 is a natural inhibitor of TGF-beta signaling. In contrast to gut T cells from uninfected mice, Foxp3-IL10-CD4+ T cells from Hpb-infected mice displayed reduced Smad7 expression and responded to TGF-beta with Smad2/3 phosphorylation. The TGF-beta-induced Tregs expressing IL10 blocked colitis when transferred into the Rag/CD25- CD4+ T cell transfer model of IBD. Thus, infection with Hpb causes down-modulation in Smad7 expression in intestinal CD4+ T cells, which allows the TGF-beta produced in response to the infection to induce the Tregs that prevent colitis.