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Intestinal dendritic cell migration and induction of T cell responses

Hägerbrand, Karin LU (2015) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2015:111.
Abstract
The intestine represents the body’s largest surface exposed to the outer world and is thus a major entry site for pathogens such as bacteria and viruses. The intestinal immune system has the important task of protecting us against infection while maintaining tolerance against the vast amount of commensal microbes populating the intestinal tract and the multitude of foreign antigen present in the diet. Intestinal dendritic cells (DCs) have a central role in maintaining homeostasis and their continual migration from the intestinal mucosa to the draining mesenteric lymph nodes (MLN) is required for the induction of adaptive immune responses to orally derived antigen as well as the development of oral tolerance to food proteins. Migratory DCs... (More)
The intestine represents the body’s largest surface exposed to the outer world and is thus a major entry site for pathogens such as bacteria and viruses. The intestinal immune system has the important task of protecting us against infection while maintaining tolerance against the vast amount of commensal microbes populating the intestinal tract and the multitude of foreign antigen present in the diet. Intestinal dendritic cells (DCs) have a central role in maintaining homeostasis and their continual migration from the intestinal mucosa to the draining mesenteric lymph nodes (MLN) is required for the induction of adaptive immune responses to orally derived antigen as well as the development of oral tolerance to food proteins. Migratory DCs are also thought to have a central role in the induction of gut-homing receptors on T cells, allowing the T cells to home to the gut and perform effector functions.

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. (Less)
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author
supervisor
opponent
  • Karlsson, Mikael, Karolinska Institutet
organization
publishing date
type
Thesis
publication status
published
subject
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2015:111
pages
84 pages
publisher
Section for Immunology, Lund University
defense location
Belfragesalen, BMC D15, Klinikgatan 32, Lund
defense date
2015-10-30 13:15
ISSN
1652-8220
ISBN
978-91-7619-190-3
language
English
LU publication?
yes
id
28992de5-6a39-42b8-b7a1-be0bb6331ee1 (old id 8051569)
date added to LUP
2015-10-06 15:04:33
date last changed
2016-09-19 08:44:45
@phdthesis{28992de5-6a39-42b8-b7a1-be0bb6331ee1,
  abstract     = {The intestine represents the body’s largest surface exposed to the outer world and is thus a major entry site for pathogens such as bacteria and viruses. The intestinal immune system has the important task of protecting us against infection while maintaining tolerance against the vast amount of commensal microbes populating the intestinal tract and the multitude of foreign antigen present in the diet. Intestinal dendritic cells (DCs) have a central role in maintaining homeostasis and their continual migration from the intestinal mucosa to the draining mesenteric lymph nodes (MLN) is required for the induction of adaptive immune responses to orally derived antigen as well as the development of oral tolerance to food proteins. Migratory DCs are also thought to have a central role in the induction of gut-homing receptors on T cells, allowing the T cells to home to the gut and perform effector functions.<br/><br>
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.<br/><br>
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.},
  author       = {Hägerbrand, Karin},
  isbn         = {978-91-7619-190-3},
  issn         = {1652-8220},
  language     = {eng},
  pages        = {84},
  publisher    = {Section for Immunology, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Intestinal dendritic cell migration and induction of T cell responses},
  volume       = {2015:111},
  year         = {2015},
}