Regulation of Intestinal Immune Homeostasis Público
Geem, Duke (2015)
Published
Abstract
The intestinal immune system interacts with a multitude of foreign antigens in the environment and must elicit appropriate pro-inflammatory or tolerogenic immune responses. Crucial to mediating host defense and immune tolerance are T-helper (Th) 17 and Foxp3+ regulatory T (Treg) cells, respectively, which are specialized CD4+ T cell subsets enriched in the lamina propria (LP). Currently, the cellular and molecular networks that regulate their development remain to be fully defined. To begin investigating the development of intestinal Th17 and Foxp3+ Treg cell responses, the tissue sites important for the differentiation of these cells must first be elucidated. As previous studies have implicated the mesenteric lymph nodes (mLN) and GALT to be the site of intestinal CD4+ T cell responses, the requirement for these structures in supporting intestinal Th17 and Foxp3+ Treg cells was examined. In lymphotoxin-deficient mice that are void of secondary lymphoid organs--including mLN and GALT, normal frequencies and absolute numbers of intestinal Th17 and Foxp3+ Treg cells was observed. These results suggested that Th17 and Foxp3+ Treg cell differentiation may occur within the intestinal LP under the regulation of local antigen presenting cells and the microbiota. Mechanistic studies of intestinal Th17 cell development following colonization by segmented filamentous bacteria (SFB) revealed requirements for MHC class II on CD11c+ cells and antigenic stimulation. This SFB-driven Th17 cell differentiation was dependent on IL-1 signaling and inhibited by eosinophils, which constitutively produced IL-1 receptor antagonist. Moreover, analysis of the Foxp3+ Treg cells in the intestine revealed site-specific differences between the small intestine (SI) and large intestine (LI) in terms of composition and reactivity. Foxp3+Helios+ thymically-derived (t)T-reg cells were the predominant population in the intestine with greater abundance in the SI than the LI. Correspondingly, conventionalization of germ-free mice robustly promoted Foxp3+ Treg cell development in the LI, but not in the SI, highlighting distinct reactivity to the gut microbiota between these two sites. Collectively, our findings define important tissue sites required for the intestinal Th17 and Foxp3+ Treg cell development and underscore the contribution of the local milieu in regulating their differentiation and function.
Table of Contents
Chapter 1: Introduction. 1
Th17 cells
A functional profile of Th17 cells
Molecular development of Th17 cells
Development of Th17 cells in vivo
Foxp3+ Treg cells
The development of Foxp3+ Treg cells
Mechanisms of immune suppression by Foxp3+ Treg cells
Regulation of intestinal Foxp3+ Treg cells by the gut microbiota
Intestinal macrophages and DCs
Development and phenotypic characterization of intestinal macrophages and DCs
Homeostatic functions of intestinal macrophages
Contributions of DCs to intestinal homeostasis
Chapter 2: Specific microbiota-induced intestinal Th17 differentiation requires MHC class II but not GALT and mesenteric lymph nodes. 28
Introduction
Materials and Methods
Naïve CD4+ T cells are present in the intestinal LP independent of LT-dependent
lymphoid structures.
Intestinal Th17 differentiation takes place in the absence of the GALT, mLN, and other LT-dependent lymphoid structures.
MHC II is required for intestinal Th17 differentiation induced by SFB-containing microbiota.
Cognate antigen promotes intestinal Th17 differentiation in the presence of SFB-containing microbiota.
Discussion
Chapter 3: Intestinal Th17 cell differentiation in response to SFB-containing microbiota is regulated by IL-1/IL-1R1 axis and eosinophils. 65
Introduction
Materials and Methods
Intestinal Th17 cell differentiation induced by SFB-containing microbiota is dependent on IL-1 signaling.
Eosinophils inhibit Th17 cell differentiation mediated by DCs and macrophages
in vitro.
Depletion of eosinophils augments intestinal Th17 cell differentiation in response to SFB containing microbiota.
Intestinal eosinophils secrete IL-1 receptor antagonist.
Discussion
Chapter 4: Foxp3+ peripheral Treg cells are more abundant in the colon relative to the small intestine and do not require the GALT and mesenteric lymph nodes. 84
Introduction
Materials and Methods
Foxp3+ Treg cells are enriched in the intestinal LP and their presence is independent of CCR7.
Intestinal Foxp3+ Treg cell development does not require the mLN, GALT, and other LT-dependent lymphoid structures.
Distinct requirements for mLN, GALT, and other LT-dependent lymphoid structures in mediating Foxp3+ Treg cell differentiation in the SI LP versus the LI LP.
Foxp3+ tTreg cells constitute majority of the Foxp3+ Treg cell reservoir in the intestine with more in the SI LP than the LI LP.
Foxp3+ pTreg cells reactive to the gut microbiota are enriched in the LI LP.
Discussion
Chapter 5: Discussion. 108
References. 121
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