Type I IFNs regulate effector and regulatory T cell accumulation and anti-inflammatory cytokine production during T cell-mediated colitis.

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Kole A, He J, Rivollier A, Silveira DD, Kitamura K, Maloy KJ, Kelsall BL

Type I IFNs regulate effector and regulatory T cell accumulation and anti-inflammatory cytokine production during T cell-mediated colitis.

J Immunol. 2013 Sep 1;191(5):2771-9. doi: 10.4049/jimmunol.1301093. Epub 2013 Aug 2.

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23913971 [ View in PubMed

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Abstract

We explored the function of endogenous type I IFNs (IFN-1) in the colon using the T cell adoptive transfer model of colitis. Colon mononuclear phagocytes (MPs) constitutively produced IFN-1 in a Toll/IL-1R domain-containing adapter-inducing IFN-beta-dependent manner. Transfer of CD4(+)CD45RB(hi) T cells from wild-type (WT) or IFN-alpha/beta receptor subunit 1 knockout (IFNAR1(-/-)) mice into RAG(-/-) hosts resulted in similar onset and severity of colitis. In contrast, RAG(-/-) x IFNAR1(-/-) double knockout (DKO) mice developed accelerated severe colitis compared with RAG(-/-) hosts when transferred with WT CD4(+)CD45RB(hi) T cells. IFNAR signaling on host hematopoietic cells was required to delay colitis development. MPs isolated from the colon lamina propria of IFNAR1(-/-) mice produced less IL-10, IL-1R antagonist, and IL-27 compared with WT MPs. Accelerated colitis development in DKO mice was characterized by early T cell proliferation and accumulation of CD11b(+)CD103(-) dendritic cells in the mesenteric lymph nodes, both of which could be reversed by systemic administration of IL-1R antagonist (anakinra). Cotransfer of CD4(+)CD25(+) regulatory T cells (Tregs) from WT or IFNAR1(-/-) mice prevented disease caused by CD4(+)CD45RB(hi) T cells. However, WT CD4(+)CD25(+)Foxp3(GFP+) Tregs cotransferred with CD4(+)CD45RB(hi) T cells into DKO hosts failed to expand or maintain Foxp3 expression and gained effector functions in the colon. To our knowledge, these data are the first to demonstrate an essential role for IFN-1 in the production of anti-inflammatory cytokines by gut MPs and the indirect maintenance of intestinal T cell homeostasis by both limiting effector T cell expansion and promoting Treg stability.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Human interferon beta	Interferon alpha/beta receptor 1	Protein	Humans	Yes	Binder	Details