The Role of M Cells in the Development of the Mucosal Immune System Open Access

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

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Biology, General
Keyword	Microbiota Immunology M cells
Committee Chair / Thesis Advisor	Williams, Ifor , Emory University
Committee Members	Denning, Timothy , Georgia State University Weiss, David S, Emory University Jacob, Joshy, Emory University Kohlmeier, Jacob, Emory University

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