The Role of M Cells in the Development of the Mucosal Immune System Open Access
Rios, Daniel (2016)
Abstract
The mucosal immune system is tasked with the unique challenge of maintaining and tolerating beneficial commensal micrbiota while simultaneously responding to and eliminating dangerous pathogens. The precise mechanisms underlying this duality have only begun to be unraveled. Extending previous findings from our lab we developed a novel model of intestinal M cell deficiency to study the role of M cells in the maintenance of homeostasis in intestinal tissues. Using this first-of-its-kind model of M cell deficiency we found two non-redundant roles for M cells in the development of the mucosal immune system. We observed that M cells were fundamentally required for the sampling of large particulate antigen into Peyer's patches (PPs) in the gut. In the absence of M cells germinal center formation in PPs was delayed resulting in a 10-14 day lag in the initiation of secretory IgA responses in the gut. These defects were not observed when M cell deficient mice were reared in the absence of commensal microbiota, indicating microbe derived antigen sampled by M cells is the primary means of initiation IgA responses in the gut. Continuing these studies we sought to characterize other immune responses in the gut in the absence of M cells. We found, unexpectedly, that the frequency and function of group 3 innate lymphoid (ILC3) cells in mice lacking PP M cells were reduced. The reduction in ILC3 combined with the delayed initiation of IgA responses in the gut resulted in an increased susceptibility of M cell deficient mice to bacterial infections immediately after weaning. These results indicate that M cells are critical, non-redundant mediators of cross-talk between host and microbiota. Further characterization M cells using this model system may provide potentially translatable insights in the mechanisms of disease pathogenesis in mucosal tissues.
Table of Contents
Abstract iv
Acknowledgments vi
List of Figures ix
Introduction 1
Overview of the mucosal immune system 1
Organization of the mucosal immune system 2
Physical barriers 3
Innate barriers 4
Adaptive immune cells 6
What is the microbiota? 7
Synergistic development of the mucosal immune system and the microbiota 10
Antigen sampling in the villous epithelium 11
Antigen sampling across the FAE 13
Development and function of M cells 14
Generation and function of mucosal IgA responses 16
What is the relationship between M cell antigen sampling and the development of the mucosal immune system 19
References 20
Chapter 1 : Antigen sampling by intestinal M cells is the principal pathway initiating mucosal IgA production to commensal enteric bacteria 28
Abstract 29
Introduction 30
Materials and Methods 33
Results 48
Discussion 55
References 60
Figures 66
Chapter 2: Differentiation and Function of Group 3 Lymphoid Cells are Compromised in Mice Lacking Intestinal M Cells 83
Abstract 84
Introduction 85
Materials and Methods 87
Results 94
Discussion 99
References 103
Figures 110
Discussion 120
References 130
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