Submitted to: European Journal of Immunology
Publication Type: Peer reviewed journal
Publication Acceptance Date: 3/15/2009
Publication Date: 6/19/2009
Citation: Ince, M.N., Elliott, D.E., Setiawan, T., Metwali, A.A., Blum, A., Chen, H.L., Urban Jr, J.F., Flavell, R.A., Weinstock, J.V. 2009. Role of T cell TGF beta signaling in intestinal cytokine responses and helminthic immune modulation. European Journal of Immunology. 39:(7):1870-8. Interpretive Summary: Parasitic worm exposure is associated with immune modulation in humans and represented in mouse models that show down-regulation of immune responses to antigens unrelated to the parasite. This response may be useful in the treatment of autoimmune and immunological diseases, like inflammatory bowel disease (IBD). Worms stimulate the host to produce a number of protein molecules called Th2 cytokines 5TET that block production of Th1 cytokine responses 3IET important in inflammation. Worms also modulate intestinal inflammatory responses, enhance immune regulation, and limit disease activity in various animal models of IBD. When mice exposed to a chemical to induce inflammation in the colon (colitis) were also inoculated with the mouse parasite Heligmosomoides polygyrus, the mice were protected from the colitis that was associated with decreased IFN Beta and IL12/23 p40 and increased IL4, IL13, and IL10 production in the intestinal tissue. The studies also demonstrated that a particular type of regulatory T cell isolated from the intestine could transfer the ability to reduced inflammation to naïve mice, and that these cells secreted an important regulating molecule called TGF Beta. This work will be of interest to those who study regulation of immune expression, but also to nutritionists and clinicians interested in regulators of intestinal function, host immunity, and nutrient absorption.
Technical Abstract: Colonization with helminthic parasites down-regulates inflammation in murine colitis and improves activity scores in human inflammatory bowel disease. Helminths induce mucosal regulatory T cells, which are important for intestinal immunologic homeostasis. Regulatory T cell function involves cytokines like TGF Beta. TGF Beta exerts major effects on T lymphocytes. This study investigated the role of T lymphocyte TGF Beta signaling in helminthic modulation of intestinal immunity in mice. T cell TGF Beta signaling is interrupted in TGF Beta RII DN mice by T cell-specific over-expression of a dominant negative TGF Beta receptor II. We studied lamina propria mononuclear cell responses in wild-type and TGF Beta RII DN mice that were uninfected or colonized with the nematode, Heligmosomoides polygyrus. We show that although helminths stimulate mucosal TGF Beta production and down-modulate inflammatory cytokine secretion in wild-type animals. Without T cell TGF Beta signaling however, the gut displays dysregulation of both Th1 and Th2 cytokines, showing that TGF Beta-T cell interactions limit intestinal Th1 and Th2 responses. Helminths stimulate interleukin-10 secretion in the intestine of wild-type, but not TGF Beta RII DN mice. Interleukin-10 normally modulates gut interferon-alpha production, but fails to do so without intact TGF Beta signaling. In vivo, H. polygyrus fails to prevent spontaneous colitis development in TGF Beta RII DN animals. Our results indicate an essential role of T cell TGF Beta signaling in helminthic regulation of intestinal inflammation and in limiting both Th1 and Th2 gut responses. Helminthic induction of intestinal IL10 and its function require intact T cell TGF Beta circuitry.