Role of T cell TGF‐β signaling in intestinal cytokine responses and helminthic immune modulation

Abstract

Colonization with helminthic parasites induces mucosal regulatory cytokines, like IL-10 or TGF-b, that are important in suppressing colitis. Helminths induce mucosal T cell IL-10 secretion and regulate lamina propria mononuclear cell (LPMC) Th1 cytokine generation in an IL-10-dependent manner in WT mice. Helminths also stimulate mucosal TGF-b release. As TGF-b exerts major regulatory effects on T lymphocytes, we investigated the role of T lymphocyte TGF-b signaling in helminthic modulation of intestinal immunity. T cell TGF-b signaling is interrupted in TGF-b receptor II dominant negative (TGF-bRII DN) mice by T-cellspecific over-expression of a TGF-bRII DN. We studied LPMC responses in WT and TGF-bRII DN mice that were uninfected or colonized with the nematode, Heligmosomoides polygyrus. Our results indicate an essential role of T cell TGF-b signaling in limiting mucosal Th1 and Th2 responses. Furthermore, we demonstrate that helminthic induction of intestinal T cell IL-10 secretion requires intact T cell TGF-b-signaling pathway. Helminths fail to curtail robust, dysregulated intestinal Th1 cytokine production and chronic colitis in TGF-bRII DN mice. Thus, T cell TGF-b signaling is essential for helminthic stimulation of mucosal IL-10 production, helminthic modulation of intestinal IFN-c generation and H. polygyrus-mediated suppression of chronic colitis. IntroductionHelminth exposure is associated with immune modulation in the human or murine host and decreased immune reactivity to antigens unrelated to the parasite [1]. This response may be useful in the treatment of autoimmune and immunological diseases, like inflammatory bowel disease [2,3]. Helminths stimulate the host to produce Th2 (IL-4, IL-5, IL-9, IL-13) or regulatory (IL-10, TGF-b) cytokines, while blocking Th1 cytokine responses [4,5].Helminthic parasites limit disease activity in various animal models of inflammatory bowel disease. For example, rectal trinitrobenzene sulfonic acid administration causes a T cell cytokinedriven colitis that is prevented by systemic administration of 1870Schistosoma mansoni eggs or duodenal colonization with Heligmosomoides polygyrus larvae [6,7]. H. polygyrus-mediated regulation of IFN-g, IL-12/23 (p40) production and protection from colitis is in part blocked by inhibiting IL-10 signaling in this trinitrobenzene sulfonic acid model. IL-10 is a major immune regulatory cytokine [8] that helps prevent intestinal inflammation. Accelerated, severe colitis is triggered in IL-10 deficient and not WT mice by Helicobacter hepaticus infection or treatment of the animals with non-steroidal antinflammatory drugs [9][10][11]. Although different cells can produce IL-10 and regulate immune responses, animal studies implicate CD4 T lymphocyte derived IL-10 as a non-redundant regulator of intestinal immune balance [12]. IL-10 is involved in helminthic regulation of mucosal Th1 cytokine responses where T cells constitute the major source of intestinal 14]. The mechanism of how helminths induce IL-10-producing T cells is unknown. ...

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Exacerbation of Oxazolone Colitis by Infection with the Helminth Hymenolepis diminuta

“…1 Collectively, these studies have shown that as a consequence of the host response to infection with helminth parasites, there is mobilization of transforming growth factor (TGF)-␤, interleukin (IL)-10, Foxp3 ϩ regulatory T cells, alternatively activated macrophages, and inhibition of IL-17-and interferon (IFN)-␥-driven events: one, or a combination, of these events could block the development of autoimmune and inflammatory disorders. [2][3][4][5][6][7] These findings have been complemented by intriguing data suggesting that infection with viable parasitic nematodes could be a treatment for patients with inflammatory bowel disease (IBD) 8 or asthma, 9 whose condition is not managed by conventional therapies.…”