The role of type I interferons in regulating intestinal inflammation
<p>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 (...
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| Formato: | Thesis |
| Idioma: | English |
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2013
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| _version_ | 1826303199462555648 |
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| author | Kole, A |
| author2 | Maloy, K |
| author_facet | Maloy, K Kole, A |
| author_sort | Kole, A |
| collection | OXFORD |
| description | <p>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.</p> |
| first_indexed | 2024-03-07T05:59:02Z |
| format | Thesis |
| id | oxford-uuid:eb8860d1-9ab9-49b9-81b4-b74b4442f2d5 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:59:02Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | oxford-uuid:eb8860d1-9ab9-49b9-81b4-b74b4442f2d52022-03-27T11:10:23ZThe role of type I interferons in regulating intestinal inflammationThesishttp://purl.org/coar/resource_type/c_db06uuid:eb8860d1-9ab9-49b9-81b4-b74b4442f2d5ImmunologyBiologyEnglishOxford University Research Archive - Valet2013Kole, AMaloy, KKelsall, B<p>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.</p> |
| spellingShingle | Immunology Biology Kole, A The role of type I interferons in regulating intestinal inflammation |
| title | The role of type I interferons in regulating intestinal inflammation |
| title_full | The role of type I interferons in regulating intestinal inflammation |
| title_fullStr | The role of type I interferons in regulating intestinal inflammation |
| title_full_unstemmed | The role of type I interferons in regulating intestinal inflammation |
| title_short | The role of type I interferons in regulating intestinal inflammation |
| title_sort | role of type i interferons in regulating intestinal inflammation |
| topic | Immunology Biology |
| work_keys_str_mv | AT kolea theroleoftypeiinterferonsinregulatingintestinalinflammation AT kolea roleoftypeiinterferonsinregulatingintestinalinflammation |