Intestinal dendritic cell migration and induction of T cell responses
Författare
Summary, in English
In this thesis I investigate the signals that drive DC migration to the MLN under homeostatic and inflammatory conditions. The results presented show that in the steady state, DC migration is driven by the adaptor protein MyD88, which mediates signaling through pattern recognition receptors of the Toll-like receptor family as well as receptors of the cytokines IL-1β, IL-18 and IL-33. While optimal DC migration requires MyD88 signaling in CD11c+ cells, including DCs, it is independent of the microbiota, caspase-1-induced maturation of IL-1β and IL-18 and signaling through the IL-18 receptor. Additionally, we find that DC migration in response to an inflammatory stimulus requires TNF-α signaling, in contrast to the steady state migration that is TNF-α independent. We further find that induction of the gut-homing receptor CCR9 on T cells in an inflammatory setting requires TNF-α signaling in stromal cells, but is independent of TNF-α-induced DC migration from the intestine. As TNF-α is involved in the pathology of inflammatory bowel disease (IBD), and TNF-α-neutralizing therapies are used in IBD with great success, these findings could aid the understanding of the mechanisms involved in intestinal inflammation and anti-TNF therapy efficacy.
Although IL-18 signaling did not drive steady state DC migration, we found that it had a role in the generation of IFN-γ producing T cells and in cytokine-induced TCR-independent innate-like cytokine production by T cells in a T cell-dependent mouse model of intestinal inflammation. Impaired IL-18 signaling in the T cells did however not have an impact on disease severity. This data could also aid the understanding of disease mechanisms in IBD.
Avdelning/ar
Publiceringsår
2015
Språk
Engelska
Publikation/Tidskrift/Serie
Lund University Faculty of Medicine Doctoral Dissertation Series
Volym
2015:111
Dokumenttyp
Doktorsavhandling
Förlag
Section for Immunology, Lund University
Ämne
- Immunology
Status
Published
Forskningsgrupp
- Adaptive Immunity
Handledare
ISBN/ISSN/Övrigt
- ISSN: 1652-8220
- ISBN: 978-91-7619-190-3
Försvarsdatum
30 oktober 2015
Försvarstid
13:15
Försvarsplats
Belfragesalen, BMC D15, Klinikgatan 32, Lund
Opponent
- Mikael Karlsson