DEVELOPMENT OF M CELLS AND SMALL LYMPHOID TISSUES IN THE INTESTINE Open Access

Knoop, Kathryn (2011)

Permanent URL: https://etd.library.emory.edu/concern/etds/9z902z97d?locale=en
Published

Abstract


Mucosal surfaces are constantly bombarded with commensal bacteria and foreign
antigen. To prevent constant inflammation, tolerance is induced to many of the foreign
antigens encountered in Peyer's patches (PP) and isolated lymphoid follicles (ILF).
Microfold cells (M cells), found as part of the follicle-associated epithelium (FAE)
overlaying the PPs and ILFs, are specialized epithelial cells that constantly transcytosing
antigen. The factors driving M cell development were previously unknown; the
commonly held model being factors from the B cells and developing follicle foster the
growth of M cells, as most M cells develop over follicles. RANKL, a member of the TNF
superfamily, has been shown to be critical in development of lymphoid aggregates
including lymph nodes and isolated lymphoid follicles. Direct interaction of RANKL+
stromal cells in the subepithelial dome and RANK+ epithelial cells on the FAE appears to
be essential to M cell differentiation.
In the absence of RANKL, M cells are reduced 98% and have a disrupted pattern
across the follicle; these changes contribute to a reduction in germinal centers in PP and
fecal IgA. Recombinant RANKL can rescue M cell development in RANKL-/- mice and
promote the development of villous M cells on all of the small intestinal villi, drastically
increasing the ability of the small intestine to take up antigens. The development of
villous M cells can also be induced by the enteric flora, specifically the enteric flora
found in mice lacking IgA. These villous M cells were dependent on systemic RANKL,
supporting a model in which the commensal microflora and RANKL coordinately
regulate the extent of vM cell differentiation in the small intestine.

Next, a model of acute B cell depletion was used to better understand the role of
B cells in M cell development. After two weeks of continuous B cell depletion, M cell
development on the PP dome is virtually unchanged. Furthermore, B cell deficient mice
maintain a wild type M cell density on the PP domes, though the absolute number of M
cells is decreased as the follicle and FAE shrinks. Finally, in the absence of RANKL
development small lymphoid tissue aggregates in the small intestine, cryptopatches and
ILFs, is disrupted. Cryptopatches are reduced four-fold, and ILFs are completely absent.
This lack of ILF development is due to the lack of CXCL13 in these aggregates and a
failure to attract B cells to the follicle. Interestingly a dependence on RANKL for
cryptopatch and ILF development is not seen in the large intestine, where CXCL13
expression is controlled by some other mechanism, perhaps the increased density of
enteric flora.
In conclusion, the data presented here suggests a new model of M cell
development in which the major signal is derived from RANKL and secondary
contributions may come from the enteric flora. Additionally, RANKL is critical in the
development of ILFs in the small intestine. These novel functions of RANKL suggest this
single cytokine is imperative in two events in the development of the mucosal immune
system. By controlling both antigen sampling within the PP and ILFs, and the
development of ILFs, RANKL is an important factor in orchestrating peripheral
tolerance. Alongside RANKL, the enteric flora exerts collaborative and partially
redundant signals to induce and maintain M cells in the FAE and ILFs.

Table of Contents

TABLE OF CONTENTS
PAGE

A

BSTRACT

ACKNOWLEDGEMENTS

LIST OF FIGURES

LIST OF TABLES

INTRODUCTION
1
RESULTS

CHAPTER 1: RANKL is necessary and
15
sufficient to initiate development of antigen-

sampling M cells in the intestinal epithelium



CHAPTER 2: Differentiation of Peyer's
59
patch M cells does not require signals from

B cells




CHAPTER 3: Escape of the enteric microflora
94
from the normal homeostatic control of secretory

IgA results in expanded development of small

intestinal villous M cells




CHATPER 4: Other examples of an
122
association of stromal RANKL and GP2+ M

cells in organized intestinal lymphoid tissues




CHAPTER 5: Distinct developmental
133

requirements for isolated lymphoid follicle
formation in the small and large intestine:
RANKL is essential only in the small
intestine




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