Intestinal homeostasis is a delicate balance between suppression of immune responses against innocuous antigens and stimulation of immune responses against pathogens. Type I interferon (IFN-1) cytokines have both immunostimulatory and immunomodulatory effects. Colon mononuclear phagocytes (MP) constitutively produced IFN-1 in a TRIFdependent manner. We explored the function of endogenous IFN-1 in the colon using the T cell adoptive transfer model of colitis. Transfer of CD4<sup>+</sup>CD45RB<sup>hi</sup> naïve T cells from wild type (WT) or IFNAR subunit 1 knockout (IFNAR1<sup>-/-</sup>) mice into RAG<sup>-/-</sup> hosts resulted in similar onset and severity of colitis. In contrast, RAG<sup>-/-</sup> x IFNAR1<sup>-/-</sup> double knockout (DKO) mice developed accelerated severe colitis compared to RAG<sup>-/-</sup> hosts when transferred WT CD4<sup>+</sup>CD45RB<sup>hi</sup> T cells. Although WT or IFNAR1<sup>-/-</sup> regulatory T (Treg) cells equally prevented disease caused by CD45RB<sup>hi</sup> naïve T cells, WT Treg cells co-transferred with naïve CD4<sup>+</sup> T cells into DKO recipients failed to expand or maintain Foxp3 expression and gained effector functions in the colon. IFNAR signaling on host hematopoietic cells inhibited T cell-mediated colitis, but not innate colitis. MPs isolated from the colon lamina propria (cLP) required IFNAR signaling for the production of the anti-inflammatory cytokines, IL-10, IL-27, and IL-1RA, but not for the production of classic pro-inflammatory cytokines. IFN-1-dependent secretion of IL-1RA was particularly important in inhibiting the migration of inflammatory DCs with potent T cell proliferative capacity from the cLP to the mesenteric lymph nodes. Finally, preliminary results suggested that IFN-1 may shape the commensal microbiota, but is not essential for controlling specific colitis-inducing bacteria.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:604447 |
| Date | January 2013 |
| Creators | Kole, Abhisake |
| Contributors | Maloy, Kevin J.; Kelsall, Brian L. |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:eb8860d1-9ab9-49b9-81b4-b74b4442f2d5 |
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