DEVELOPMENT OF M CELLS AND SMALL LYMPHOID TISSUES IN THE INTESTINE Open Access
Knoop, Kathryn (2011)
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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