Induction of T helper 2 cell responses against Schistosoma mansoni eggs in the murine intestine

Mayer, Johannes Urban (2017) Induction of T helper 2 cell responses against Schistosoma mansoni eggs in the murine intestine. PhD thesis, University of Glasgow.

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Abstract

T helper 2 (Th2) cell responses typify the immune response to parasitic organisms, which frequently invade the intestine. Dendritic cells (DCs) are considered vital for the induction of Th2 responses as they present parasite- derived antigens to naive T cells in draining lymph nodes. However, the identities of the DC populations responsible for priming Th2 cells in the intestine are still unclear. We developed an experimental immunization protocol to deliver Schistosoma mansoni eggs into the intestine. During live infection by the parasite, these eggs cause intestinal damage, granuloma formation, tissue fibrosis and strong type 2 immune responses. Many aspects of type 2 immunity are controlled by the transcription factor IRF4 and we observed that intestinal Th2 responses against Schistosoma mansoni eggs did not develop in the draining lymph nodes in the absence of IRF4+ DCs. IRF4f/f CD11c-cre positive mice had fewer CD11b-expessing migrating DCs, and fewer parasite antigen-carrying DCs were present in the mesenteric lymph nodes (MLNs) draining the small intestine and colon. However, transfer of antigen-loaded IRF4-deficient DCs directly into the MLN revealed that these cells could induce antigen-specific Th2 responses, suggesting that IRF4 controlled the migration of CD11b-expessing DCs rather than their Th2 inducing capacity. Furthermore, immature DCs from the intestinal lamina propria, and semi-mature DCs from lymph were sufficient to prime antigen-specific Th2 responses against egg antigens when transferred into naive recipient mice. This induction was dependent on MHCII expression but not on the production of IL-4 by the transferred DCs, indicating that conventional intestinal DCs are fully capable of inducing Th2 responses against S. mansoni egg antigens upon transfer. Further analysis of migratory small intestinal and colonic lymph DCs revealed that distinct subsets of CD11b-expressing DCs were sufficient for the induction of Th2 responses in the small intestine and colon. CD11b+CD103+ DCs transported parasite antigen from the small intestine, whereas CD11b+CD103- DCs performed this role in the colon. Of note, these same small intestinal and colonic DC subsets were also the populations that were most efficient at priming antigen-specific Th2 responses in vivo. Thus, we have not only identified that IRF4-dependent CD11b-expressing DCs are specialized to drive Th2 responses in the intestine but have also revealed that different DC subsets promote Th2 responses in the small intestine and colon. These findings not only advance our knowledge of intestinal Th2 responses against parasite antigens but also reveal a hitherto unappreciated functional heterogeneity among intestinal DCs, which could also be relevant for other tissue- specific intestinal conditions like Crohn’s disease, ulcerative colitis and celiac disease.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Dendritic cells, Th2 responses, murine intestine.
Subjects: Q Science > QR Microbiology > QR180 Immunology
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation > Immunology
Funder's Name: UNSPECIFIED
Supervisor's Name: Milling, Dr. Simon
Date of Award: 2017
Depositing User: Johannes U Mayer
Unique ID: glathesis:2017-7972
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 14 Mar 2017 14:04
Last Modified: 01 May 2017 08:28
URI: http://theses.gla.ac.uk/id/eprint/7972

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