Review

Received: February 19, 2002

Pathobiology 2002–03;70:55–68
Accepted: July 29, 2002
DOI: 10.1159/000067305

Peyer’s Patches: Organized Lymphoid

Structures for the Induction of Mucosal
Immune Responses in the Intestine
L.H.C. Makala N. Suzuki H. Nagasawa
National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine,
Hokkaido, Japan

Key Words Background

Distribution W Structure W Ontogeny W Immune response W
IgA
Abstract
Peyer’s patches (PP) comprise transmucosal clusters of
lymphoid follicles overlaid with a specialized lympho-
epithelium and consequently play a central role in the
induction of mucosal immune responses in the gut.
Despite considerable achievements in the last 3 decades,
in our understanding of how PP are involved in the
induction of immune responses, much remains to be
learned about these major organized lymphoid organs.
The history and current status of PP termed ‘the major
inductive site of immune responses’ is reviewed. The
present understanding of PP biology and function, taking
into account their preferential and unique retention of
immune competent cells at specific sites, is discussed.
Copyright © 2002 S. Karger AG, Basel
Joseph Hans Conrad Peyer, a Swiss anatomist and
physician (1653–1712) in 1677 provided the first accurate
description of the discrete lymphoid aggregates in the
intestinal wall, which have come to bear his name [1, 2].
In the mid-19th century, Brucke provided illustrations of
the microscopic appearance of Peyer’s patches (PP) in
dogs and cats, also noting that the tissues were organized
into discrete follicles, surrounded by connective tissue [3].
Three decades later, Fleming established that PP were
localized sites of intense lymphocyte division and consid-
ered the reactive centres in lymph nodes and PP follicles
to be similar [4]. Thus began the convention, which most
immunologists still follow to date that the specialized sites
of lymphocyte division in lymph nodes, spleens and PP
follicles were germinal centres. Later, Carlens [5] made
the important observation that PP of cows, sheep, pigs
and horses developed at specific regions of the gut during
fetal life and that after birth they had distinctive develop-
mental patterns. These structures have also been termed
intestinal tonsils or aggregated follicles [reviewed in 2, 6–
8]. Early research concentrated on describing the anatom-
ical distribution of PP along the intestine and their histol-
ogy. The expansion of cellular immunology in the late
1960’s and the definition of the role of T and B lympho-

© 2002 S. Karger AG, Basel H. Nagasawa, MD

ABC 1015–2008/02/0702–0055$18.50/0 National Research Center for Protozoan Diseases
Fax + 41 61 306 12 34 Obihiro University of Agriculture and Veterinary Medicine
E-Mail karger@karger.ch Accessible online at: Inada-Cho, Obihiro, Hokkaido 080-8555 (Japan)
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Table 1. Names, dates, scientific findings and theories that emerge in the history of the development of Peyer’s patches

Authors Dates Scientic finding/theory Reference

Peyer 1677 PP are mucus-secreting lymphoid aggregates 1

Brucke 1851 PP are discrete lymphoid follicles connected to lymphatics and surrounded 3
by connective tissues
Fleming 1885 PP are localised sites of lymphocyte division and found to have similarities 4
with germinal centres
Carlens 1928 jejunal (discrete) PP and ileal (continuous) PP have distinct developmental 5
patterns
Cooper and Lawton 1973 PP are sites of antigen handling and induction of IgA mucosal immune 11, 13
Craig and Cebra 1971 responses and other immune responses
Griebel and Hein 1996 PP are a site for the systemic B cell pool and generation of the primary 6–8, 24, 25
Neutra et al. 2001 immunoglobulin repertoire and PP lymphocytes also play a key role in 56, 57
Kraehenbuhl and Neutra 2000 induction of lympho-epithelium and M cells
Reynolds 1985
Reynolds et al. 1985
Kerneis et al. 1997, 2000

Data obtained from paper referenced in the text [6].

cytes gave great impetus to studies on the function of lym-
phoid tissues in mammals that may be secondary organs
from which progenitors involved in the regulation of
immune responses may be derived. It is also important to
mention that, beyond the original structural and morpho-
logical studies conducted 20–25 years ago, very little work
has been carried out on the structure and morphology of
PP in mammals in the last decade. It is generally accepted
that PP are important structures in the gut wall for the
initiation of immune reactions. However, major species
differences have often been ignored and recent progress in
understanding the regulation of M cell development and
antigen uptake is often not included in textbooks of
immunology. Therefore, the need for a review on the
structure and function of PP cannot be overemphasized.
Most of the recent work on PP has been biased towards
the role of Peyer’s patch B cells as a source of IgA precur-
sor cells and the role of Peyer’s patch T cells as regulating
cells involved in the control of immunoglobulin isotype,
both of which will be discussed in a later section of this
review.
Extensive studies have been carried out on the bursa of
Fabricus in birds which is similar in some respects to PP.
The bursa is a hollow plicated sac, which contains a large
number of lymphoid follicles. It is connected to the cloaca
by a narrow canal, the bursal duct. The bursa is the major
follicular lymphoid tissue in the intestine of birds and it
can be removed easily. From experiments with bursec-
tomized chickens it was shown that the bursa has a major
role in antibody production [9]. Experiments in which
chickens were either bursectomized or thymectomized
suggested that the cells concerned in humoral antibody
responses and cell-mediated immune responses were de-
rived from the bursa of Fabricus (B cells) and thymus (T
cells) respectively [10]. It has been suggested that lym-
phoid follicles in the gut of mammals may serve a similar
function as the bursa in birds [reviewed in 11]. In pig,
sheep and cattle, the ileal PP (IPP) probably still serves
this function. However, some studies indicate that in
most mammals, cell from a number of organs are able to
differentiate into antibody producing cells [12]. Previous
and recent studies have demonstrated that PP are a source
of precursor cells for IgA production [13–16]. The names,
dates and scientific findings and theories that emerge in
the history of the development of PP are summarized in
table 1.
Distribution and Structure of the
Peyer’s Patches
PP comprise transmucosal clusters of lymphoid folli-
cles in the small intestine, which appear ellipsoidal when
viewed from the serosal surface of the small intestine. In

56 Pathobiology 2002–03;70:55–68 Makala/Suzuki/Nagasawa

Table 2. Distribution and development of
Peyer’s patches in the different species Species Number of Peyer’s patches Development Reference
that have been studied ileum jejunum

Guinea pig 18–23 postnatal 80, 90

Rat 15–22 postnatal 2, 63, 79, 94
Rabbit sacculus rotundus 2–10 postnatal 13, 21, 27, 29, 98, 99
Human several 150–250 prenatal 22
Horses several 240–320 prenatal 5
Cattle single 25–45 prenatal 5, 17, 27
Sheep single 25–40 prenatal 5, 26, 61
Mice 5–14 postnatal 26, 28, 61, 89
Pig single 11–33 prenatal 18–20, 23, 30, 60, 111
Dog single 25–30 prenatal 78
Chicken (birds) bursa of Fabricius 2–4 postnatal 9–11

Data were obtained from papers referenced in the text (note – the PP equivalent in birds is
the bursa of Fabricius).

Table 3. Compartments,
sub-compartments and the main cell Compartments Sub-compartments Main cell types
types in a typical Peyer’s patch lymphoid non-lymphoid

Follicle1 corona T & B cells

medulla small T and B cells follicular dendritic
cortex lymphoblasts cells, macrophages
Inter-follicular area1–3 – T lymphocytes interdigitating
dendritic cells (IDC),
macrophages
Dome1, 2 – plasma cells macrophages
B cells IDC
T cells monocytes
Lympho-epithelium1 – T and B cells M cells, enterocytes
plasma cells

Data were obtained from papers referenced in the text [20, 54].
IDC = Interdigitating dendritic cells.
1 Fibroblastic reticulum cells usually are found present in all the above compartments.
2 Reticular and collagen fibers are abundant in the dome and inter-follicular areas.
3 High endothelial venules are located in the inter-follicular areas.

rats, PP are usually 3–4 mm long [2] but in larger animals,
for example cattle, PP may extend up to 4 m along the
intestine [17]. PP numbers vary between species [18–20]
and they are located along the anti-mesenteric margin of
the intestine [17]. In rabbits 5–9 PP are normally present
[21], whereas in man there may be as many as 100–300
[22]. Studies in humans [22], sheep, horses [5] and cattle
[17] have shown that the ileum has the greatest density of
PP. In pigs, sheep and cattle there are two separate types
of PP [17, 23–25]. In these species a large continuous PP
extends along the terminal segment of the intestine. In
sheep this patch extends for 2–3 m and involutes at about
1 year of age [26] and in cattle it extends for up to 4 m
along the terminal ileum. The inter-host species compari-
son of the distribution and development of PP in which
PP have been studied are shown in table 2. From the spe-
cies studied in sufficient detail (table 3), it is possible to
define two broad groups with distinct anatomical and

Peyer’s Patches: Organized Lymphoid Pathobiology 2002–03;70:55–68 57

Structures
Fig. 1. A simplified diagrammatic represen-
tation of the transverse section of a typical
Peyer’s patch, showing compartments. (Data
were obtained from papers referenced in the
text [20].)
developmental patterns in terms of the amount of PP tis-
sue found in different segments of the small intestine. The
first group (I) includes ruminants, pigs, dogs, horses and
humans [6]. In these, PP are unequally distributed along
the small intestine, with more occurring in the ileum than
in the jejunum. Moreover, in these species, the IPP occurs
as a single continuous aggregation of lymphoid follicles,
commencing at or near the ileo-cecal junction and extend-
ing cranially for a variable distance. In group II species,
namely rabbits, rodents and chickens (birds), the distribu-
tion of PP occurs at more or less random intervals along
the ileum and jejunum [2, 27]. While the development of
PP in group-I species is prenatal, the development of
group II species is postnatal. Some group II species,
namely the rabbit and the birds have a specialized gut-
associated lymphoid tissue in other regions of the intes-
tine, i.e., the sacculus rotundus and an exaggerated appen-
dix in rabbits, and the bursa of Fabricius in chicken. Work
has shown that in species with a large terminal ileum PP,
the function of this structure is probably quite different
from that of discrete PP (DPP) [26]. The involvement of
the ileal PP in B cell differentiation has been reported.
This may likely be its function. In sheep the jejunal or
58 Pathobiology 2002–03;70:55–68
DPP, approximately 25–35 in number, are comparatively
small, are distributed along the jejunum and proximal
ileum and are persistent throughout life.
Detailed histological studies of PP have been carried
out in mice [28], rats [2], rabbits [29], cattle [27] and
sheep [26]. In pig, work has been carried out on the mor-
phology, numbers and sizes of PP [19, 20, 30]. A trans-
verse section of a typical PP and its cell types are shown
diagrammatically in figure 1, as illustrated in our pre-
vious work [20]. The follicles of PP are usually pear
shaped. The region between the follicle and the lympho-
epithelium is called the dome. The lymphoid cells in the
dome are mainly T cells, plasma cells, interdigitating den-
dritic cells and tangible body macrophages as demon-
strated in previous and recent studies [19, 27, 28, 31–33].
In rabbits, rats and mice the majority of epithelial cells
overlying the dome and the follicles have a microvillus
brush border, but 20–30% have microfolds at the luminal
surface and have been called microfold or M cells [12].
The lympho-epithelium or follicle-associated epithelium
of PP in rats, mice and rabbits [34–36] contain B and T
lymphocytes than villous epithelium. Moreover, a few
plasma cells have been reported to occur in the rat M cell
Makala/Suzuki/Nagasawa
Fig. 2. Photomicrographs of indirect immu-
noperoxidase stained sections of pig discrete
Peyer’s patches at 35 days of age (!150)
showing leukocytes expressing: A CD2
(MSA4); B CD3 (FY-1HZ); C SwC3
(742215); D MHC class II – SLA-DR
(MSA3). SwC3 (742215) is a monocyte/gran-
ulocyte marker sometimes known as the my-
eloid marker. Cluster of differentiation (CD)
or swine workshop cluster number (SwC3)
designating specificity of the antigens used.
The clone numbers are shown in brackets as
sanctioned by the Veterinary Immunology
Committee of the International Union of
Immunological Scientists. LE = Lympho-
epithelium; DO = dome; FO = follicle; IFA =
inter-follicular area.

pockets [37]. Although M cells have been studied for more
than 20 years, clear-cut definitions for the identification
of M cells independent of species and location do not
exist. In order to study M cells on a light microscopic lev-
el, several groups established histochemical markers that
detect cytoplasmic or membrane-bound molecules spe-
cific for M cells. Current markers include enzymatic
activities, unidentified proteins that are bound by mono-
clonal antibodies, cytoskeletal perculiarities, and certain
terminal saccharides of glycoproteins and glycolipids [re-
viewed in 38]. The ultra-structure and several immuno
and lectin histochemical properties of M cells vary ac-
cording to species and locations along the intestine [38].
Lectins detecting fucose or N-acetyl-galactosamine selec-
tively labelled M cells in rabbit cecal patches [39, 40] and
in BALB/c mice lectins of Ulex europaeus (UEA-1) and
Lotus tetragonolobus (LTA) [41, 42]. However, it is still
unclear whether the detection of M cells by lectins can be
generalized or restricted to certain species and sites of
GALT. In other studies, Gebert et al. [40] showed that

Peyer’s Patches: Organized Lymphoid Pathobiology 2002–03;70:55–68 59

Structures
vimentin, an intermediate filament protein, is expressed
in rabbit M cells in addition to cytokeratin [43], especially
cytokeratin peptides 18 and 19. In the mouse, M cells
express MHC class II antigens and IL-1 as is the case with
other epithelial cells and they have been shown to play an
important role in transporting luminal antigens into PP
[reviewed in 7, 8, 44–47]. Bockman and Cooper [48]
showed that colloidal carbon and ferritin in the lumen of
the intestine were taken up by epithelial cells associated
with PP of the mouse. The epithelial cells associated with
the adjacent villi did not take up any of this material. In
some circumstances villous epithelial cells have been
found to take up material from the lumen of the intestine
[49], but it seems this activity is small by comparison to
the epithelial cells overlying the follicles of the PP. In
experiments involving the morphometric analysis of lyso-
somes in M cells, Owen et al. [50] established that the
small volume fraction of dense bodies (lysosomes) in M
cells provides an explanation for transport of luminal
material across the epithelium by M cells without lyso-
somal degradation. Both soluble molecules, for example,
horseradish peroxidase [51] and viable micro-organisms,
for example Salmonella typhimurium [52], have been
shown to be taken up by M cells after entering PP in mice.
These observations are consistent with the hypothesis that
M cells provide controlled transport of undegraded-lumi-
nal particles and macromolecules into lymphoid follicles
for immunologic surveillance and initiation of appro-
priate immune responses [7, 8, 53–55]. Kerneis et al. [56]
assessed the ability of PP lymphocytes to convert entero-
cytes into M cells. In a series of experiments the authors
were able to show that when lymphocytes freshly isolated
from PP were injected into the duodenal mucosa of recip-
ient mice at sites lacking organized lymphoid tissues, PP-
like structures had developed. In a more recent study,
Kerneis et al. [57] showed that PP lymphocytes co-cul-
tured with Caco-2 cells trigger the phenotypic conversion
of enterocytes into M cells that express morphological and
functional M cell properties [reviewed in 57]. Given this
stimulating and provocative data on the induction of M
cells by lymphoid cells, it should now be possible to iden-
tify signals produced by lymphocytes responsible for M
cell function, to help characterize the mechanisms me-
diating cytoskeletal re-organization and transcytosis as
well as analyse the cellular machinery mediating micro-
organism translocation through M cells, thus facilitating
the design of oral vaccines and efficient mucosal drug
delivery systems. These observations support the hypoth-
esis that PP lymphocytes play a key role in the induction
of lymphoid follicle associated epithelium and M cells.
60 Pathobiology 2002–03;70:55–68
The dome of the PP extends through a channel in the
muscularis mucosa and expands in the submucosa to
form the bodies of follicles. Pollard and Sharon [58]
described this region in mouse as a germinal zone and
there are similarities with the germinal centres found in
the lymph nodes and spleens. In the mouse, the medullary
zone of the PP follicles contain small lymphocytes (B and
T cells), lymphoblasts, follicular dendritic cells and mac-
rophages [28]. Macrophages are presumed to be the cells
responsible for the uptake of carbon in mice chronically
fed carbon in their drinking water [59]. In mice and rab-
bits the medullary zone of PP is surrounded serosally and
laterally by a cortical zone containing small lymphocytes,
blast cells and many mitotic cells indicating that this is the
region where cell proliferation is occurring [27]. The
medulla of the follicle is separated from the dome region
by a dense cuff of small lymphocytes called the corona
[27, 31].
The body of the follicle in the submucosa is sur-
rounded by a connective tissue-sheath and the region
between the follicles is referred to as the interfollicular
area (IFA). In the rabbit appendix [27, 31] and in some PP
in calves [27], adjacent follicles are separated by only a
narrow connective tissue space, which contains blood and
lymph vessels. However, the follicles of most PP are sepa-
rated from each other by a densely packed region of lym-
phoid cells, which extends from the muscularis mucosa to
the submucosa. This region contains mainly macrophages
and interdigitating cells, small lymphocytes and blast cells
[27, 28]. Small numbers of plasma cells [28], macrophages
[28, 29] and mitotic cells [31] have also been found in this
region. B and T cells leave PP out of the mucosa via effer-
ent lymphatics and into the blood circulation. Thereafter,
these cells enter the cysterna chyli, returning the cells to
the venous circulation via the thoracic duct re-entering
the intestine via high endothelial venules in the IFA. The
compartments, sub-compartments and the main cell
types in a typical PP are summarized in table 3.
Ontogeny of Peyer’s Patches
Follicles have been identified by mid gestation in the
intestine of pigs [60] and sheep [26, 61]. However, they do
not appear until around the time of birth in mice [62], rats
[2, 62] and rabbits [27]. Recent data using knockout mice
has shown that formation of PP requires complex interac-
tions between the gut epithelium, the mesenchyme, and
bone-marrow-derived hematopoietic progenitors and this
has provided insight into the molecular nature of the sig-
Makala/Suzuki/Nagasawa
nals that mediate PP ontogeny [64, 65]. In a series of
experiments, the authors have shown that PP are first vis-
ible at approximately 15.5 weeks gestation after which
there is a rapid spurt in the development and maturation
of lymphoid follicles so that at any given point of time
new foci of PP development are continuously formed at a
rapid rate. Brandtzaeg [66] and Brandtzaeg et al. [67]
summarized mechanisms for induction of specific local
immunity, with emphasis on the molecular events that
determine the distribution of primed lymphoid cells to
provide adaptive mucosal surface defence in humans. In a
series of studies in humans, they concluded that adaptive
immune protection of mucuous membranes is provided
mainly by secretory IgA (sIgA) antibodies [67–71]. Partly
because human IgA lacks ordinary complement activat-
ing properties, immune exclusion performed by sIgA anti-
bodies in principally a noninflammatory protective mech-
anism [69]. This first line of defence is accomplished
through an ingenious cooperation between the mucosal B
cell system and the epithelial glycoprotein called secretory
component (SC). This is quantitatively the most impor-
tant receptor of the immune system because it is responsi-
ble for external transport of locally produced polymeric
IgA (pIgA). Polymeric IgA has been shown to bind to the
J-chain in the region of contact between 7S monomers of
sIgA [72–74] and mediates the transcytosis of IgA to the
luminal surface of the epithelium [75–77]. The B cells
responsible for the local pIgA production are initially
stimulated in lympho-epithelial structures, particularly
the PP in the distal small intestine, from which they
migrate as memory cells to exocrine tissues all over the
body.
Studies in pigs have shown that at birth PP are visible
to the naked eye and histologically they are composed of
mononuclear cells [19, 20, 60]. In both mice and rabbits
the follicles are small at the end of gestation but after birth
they increase rapidly in size and differentiate into distinct
zones [60]. The rapid postnatal development of the folli-
cles in these species suggest that this may be in response to
luminal antigens [20]. Despite the proximity of the gut-
associated lymphoid tissues (GALT) to antigens in the
intestinal lumen, the evidence that the development of
these tissues is influenced by antigenic stimulation is
uncertain and conflicting [11]. The proximity of PP lym-
phoid follicles to the highly antigenic contents of the intes-
tine has led to the suggestion that the high rate of prolifer-
ation in these areas may be due to antigenic stimulation.
It is still uncertain what effect, if any, antigen has on PP.
Follicular differentiation of PP has been reported to
occur in utero in dogs [78]. It is likely therefore, that anti-
Peyer’s Patches: Organized Lymphoid
Structures
genic stimulation could bring about differentiation in
these species. The development of PP has been studied
after birth in germ free environment mice [58], rats [79]
and guinea pigs [80]. Each of these studies showed that if
animals are kept in a germ free environment, PP remain
small and do not differentiate, but in a conventional envi-
ronment, PP take a normal appearance [81]. In gnotobiot-
ic pigs, Pabst et al. [18], and in large white landrace pigs,
Makala et al. [20] established that age and microbial con-
tent of the gut both influence the size of the PP, but their
numbers and position remain constant.
The relationship between the development of PP and
response to antigen can, in some aspects, be deduced from
studies of the appendix tissue, which has certain structur-
al similarities to PP. The effect of antigen on the develop-
ment of PP and the appendix has also been studied by
isolating intestinal lymphoid follicles from the intestinal
contents. Stramignoni et al. [82] ligated the appendix half
way along its length in rabbits 4 h after birth. In these ani-
mals the intestinal contents had no access to the distal half
of the appendix whereas they could enter the proximal
half. During the first week the development of PP was
normal in the isolated segment and the follicles grew to a
moderate size. During the second week the follicles in the
normal segment of the appendix became very large and
differentiated into cortex and medulla. In the isolated seg-
ment the follicles grew slowly and failed to show this dif-
ferentiation. It could be suggested from this work that the
development of the lymphoid follicles depends on stimu-
lation by bacterial antigen [20, 58] in conjunction with
normal intestinal microflora [20, 83]. However, it is
doubtful whether such a general conclusion can be ex-
tended to all species, especially those in which PP have
been reported to mature before birth.
Induction of Immune Responses by
Peyer’s Patches
Evidence exists that mucosal PP are the primary site of
antigen handling [15, 16, 19, 20, 84–88]. Certainly the cell
types, which have become associated with the induction
of immune responses can be recognised in PP [20, 33] (fig-
ure 2). B cells have been demonstrated in PP of mice [89],
guinea pigs [90] and rabbits [91]. T cells have been dem-
onstrated in PP of mice [92], although Perey and Gutt-
man [93] have shown that cells derived from PP do not
have the same capacity for mediating a graft-versus-host
response as T cells obtained from the other lymphoid tis-
sues. T cells have also been identified in PP of guinea pigs
Pathobiology 2002–03;70:55–68 61
[90], in rats [94] and rabbits [95]. The fact that specific
lymphocyte subsets and APC are essential for various
immune reactions and have to lie in close vicinity cannot
be over-emphasized. Therefore it is important to know
the subset composition of lymphocytes in PP dome epi-
thelium. Here, per 100 Ìm of epithelium, 3.6 lympho-
cytes were seen in specific pathogen free mice and 11.3
lymphocytes in conventional mice [96] indicating the
stimulating effect of microbial antigens. In adult rats, two
times more lymphocytes were found in the epithelium of
the domes than that of the villi [34]. In humans, an even
higher difference was demonstrated, but with a greater
inter-individual variation, e.g., a median of 3.0 lympho-
cytes (range 2.1–5.3) per unit area of the dome epithelium
in contrast to 1.2 (range 1.0–1.6) for the villus epithelium
[37]. In rats, the lymphoid cells associated with M cells
were distributed as follows: 15 B 3% small lymphocytes,
24 B 3% medium lymphocytes, 16 B 4% immunoblasts,
and 5 B 1% plasma cells [34, 38]. The ratio of helper to T
cytotoxic lymphocytes is 0.6:10 in the villus, but 4:10 in
the dome epithelium, which indicates a much higher fre-
quency of T helper cells in the dome epithelium [37]. In a
more recent report by the same group, nearly three quar-
ters of all T cells in the dome epithelium were found to be
T helper cells (CD4+, range 40–90%) [54]. In similar stud-
ies, Andersen et al. [97] systematically characterized pig
IPP follicular lymphocytes and showed that about 90% B
cells were positive for surface immunoglobulin G (sIgM+)
and expressed an immature phenotype characterized by
the expression of a myeloid marker sWC3 (74-22-15) and
two molecules recognized by IPP B cell specific mono-
clonal antibodies (F4/4, F12/35). In a series of experi-
ments the authors concluded that pig IPP were equivalent
to sheep IPP.
Contradictory evidence for the existence of antigen-
presenting cells (APC) in PP was provided by early work.
In the PP of rabbits all the cells needed for the induction
of immune responses are present [29]. Henry et al. [98]
showed that cell cultures prepared from rabbit PP pro-
duced plaque-forming cells in vitro when mixed with
sheep erythrocytes. The same study showed a lack of
response to this antigen in vivo, perhaps an indication of
the compartmentalization of the various cell types essen-
tial in the induction of an immune response in PP. In con-
trast to these results, Kagnoff and Campbell [99] showed
that suspensions of cells from mouse PP did not give rise
to specific antibody-forming cells when mixed with heter-
ologous red blood cells. When peritoneal macrophages
were added to the cell suspension, antibody-forming cells
appeared. Kagnoff and Campbell [99] suggested that the
62 Pathobiology 2002–03;70:55–68
PP of mice were unable to respond to antigen because the
T cells and B cells of the patch were denied access to mac-
rophages or dendritic cells.
However, more recent reports indicate that cells within
the PP can take up and present antigens to local T cells or
transport them to other sites for subsequent processing
and/or presentation. The capability of the intestinal cells
to take up and transport antigens is supported by the find-
ing that veiled cells migrating from rat and mouse intes-
tine are capable of transporting bacterial antigens in rat/
mouse infected with Salmonella typhimurium [100]. Kel-
sall and Strober [101, 102] have demonstrated the pres-
ence of two populations of PP dendritic cells in mouse,
one of which forms a dense layer just beneath the dome
epithelium and another phenotypically distinct popula-
tion in the IFA. In this study PP dendritic cells were
shown to be capable of inducing proliferation in T cells in
vivo and vitro, suggesting that the DC population in the
PP are uniquely positioned for the processing of antigens
and that PP dendritic cells are effective at processing and
presenting antigens to naı̈ve T cells. It is likely then, that
the induction of intestinal immune responses can take
place in PP. It is now generally accepted that cells from
PP, when stimulated by antigens, do not mature into anti-
body forming cells until they migrate to other regions of
the body.
Migration of Cells to Peyer’s Patches
In experiments with parabiotic chick embryos in which
a chromosome marker was used to identify cells of one of
the pair have shown that cells in the embryonic bursa of
Fabricius are migratory cells derived from the circulation
[103]. Although conclusive evidence has not been ob-
tained it seems likely that cells in the developing intestinal
follicles of mammals are also cells, which migrate to these
tissues from the blood.
The generation of IgA responses involves the migra-
tion of B and T cells from PP out of the mucosa and into
the blood circulation, re-entering the intestine via high
endothelial venules in IFA and residing finally in the la-
mina propria (LP) as fully differentiated cells [13, 104]. In
a recent study, Bowman et al. [105] showed that thymus
expressed chemokine (TECK), CCL25 is a potent and
selective chemo-attractant for IgA antibody secreting
cells, efficiently recruiting IgA producing cells from
spleen, PP and MLN which may help target IgA produc-
ing cells to the gut wall, thus helping to define and segre-
gate the intestinal immune response. Extra-vascular re-
Makala/Suzuki/Nagasawa
cruitment of immune and inflammatory cells is controlled
by dynamically regulated complementary adhesion mole-
cules and chemokines expressed on the surface of circulat-
ing leucocytes and on the endothelium of venules. Such
molecules regulate the trafficking (recirculation) of naı̈ve
lymphocytes through organized lymphoid tissue and par-
ticularly the homing of primed B and T cells to immuno-
logical effector sites, such as the mucosae, as well as the
extravasation of different leucocytes in inflammation
[106, 107]. Experimental data has shown that certain lym-
phoid adhesion molecules are more strongly expressed by
unprimed (naı̈ve) than primed (memory) lymphocytes. It
is well documented that the adhesion molecule (MAD-
CAM-1) is shared between PP and the LP and also shows
considerable expression on HEV in the mesenteric lymph
nodes [108]. The molecular mechanisms directing the
integrated dissemination of immune cells from the gut
associated lymphoid tissues to exocrine sites beyond the
gut are poorly defined, although they form the functional
basis for several desired oral vaccines [109]. In sheep and
cattle the pathway taken by migratory lymphocytes has
been well described [reviewed in 110]. However, McFar-
lin and Binns [111] established that the pig has a unique
structure of MLN, which enables PP derived lymphocytes
in afferent lymph to enter the blood circulation within the
MLN. In all other species examined, the migrating cells
leave the MLN in efferent lymph and enter the cysterna
chyli, returning the cells to the venous circulation via the
thoracic duct.
Gowan and Knight [112] first showed that small lym-
phocytes obtained from the thoracic duct lymph of rats
and infused intravenously accumulated in PP. This obser-
vation has since been extended to show that the migration
of thoracic duct lymphocytes occurs selectively to differ-
ent regions of the PP [113]. Thus, blast cells obtained
from the thoracic duct lymph of rats localised in the LP of
villi between follicles of the patch and occasionally in the
IFA of PP. They never accumulate in the lymphoid folli-
cles [114]. Similar data were obtained in rabbit by Perey
and Milne [115]. Howard et al. [116] made similar obser-
vations in the rat. They showed that lightly labelled cells
accumulated in a band around the medulla, especially
towards the mucosa in the region equivalent to the dome
and corona in rabbits. In addition, cells from the thoracic
duct lymph of rats, which had been thymectomized,
lethally irradiated and reconstituted with bone marrow
had similar migratory properties to those of the lightly
labelled cells in the thoracic duct lymph of normal rats.
Few heavily labelled cells were located in IFA of PP when
injected cells were from thymectomized rats. They con-
Peyer’s Patches: Organized Lymphoid
Structures
cluded from these results that the lightly labelled cells
were derived from the thymus. These results suggest that
the IFA is a T cell area.
The structural architecture of the patch was further
defined by studies analysing migration of injected cells to
different patch tissues, for example the IFA was clearly
defined as a T-dependent area [27, 117]. It has been
shown in the mouse that labelled thymocytes migrate to
the T-dependent IFA of PP [117–120]. A similar distribu-
tion of thymus-derived cells was observed when calf thy-
mus cells were labelled in vivo by injecting 3H-thymidine
directly into the thymus [27]. Experiments in mice [89]
and rabbits [121] have shown that most cells in the IFA of
PP have thymic antigens on their surface. Calkins et al.
[95] used cells from the IFA of the rabbit appendix and
showed that many of the cells responded to the T cell
mitogen, PHA, while few were sIg+, again supporting the
view that the IFA is a T cell compartment. There is cell
traffic within the IFA [reviewed in 89]. Lymphocytes are
thought to migrate from the blood into the tissues of the
IFA via post capillary venules [122]. The importance of
the thymus in the development of the IFA has also been
shown in observations made on lambs thymectomized in
utero [123]. The IFA in these animals were small and acel-
lular, correlating with lower rate of migration of cells into
the area, because after thymectomy the recirculating pool
contains fewer lymphocytes [124].
With regard to patch follicle, Parrot and Ferguson
[117] studied the migratory properties of bone marrow
derived cells obtained from the spleen of mice which had
been thymectomized, lethally irradiated and transfused
with cells obtained from the bone marrow. On re-injec-
tion the labelled cells were shown to localise in the medul-
la of the follicles of the PP. Bone marrow-derived cells
obtained from the thoracic duct lymph of rats, localize in
a similar way following their injection intravenously
[116], as none marrow-derived cells in the rabbit do [125].
However, in the rabbit these cells accumulated in the cor-
ona of the follicles in the appendix [125]. Calkins et al.
[95] teased cells from the corona and the dome region of
the follicles of the rabbit appendix and showed that they
were IgA+ and IgM+. Studies have shown that the medul-
lary zone of PP follicles contain small lymphocytes, blast
cells and plasma cells [28] suggesting that the follicle con-
tains both B and T cells.
Little is known about the movement of cells between
the different regions of the follicle. During development,
the dome region expands to form the follicle [2] and
experiments on regeneration of the rabbit appendix after
X-irradiation have also been interpreted to indicate that
Pathobiology 2002–03;70:55–68 63
cells migrate from the dome to the follicle [126]. From
observations on the structure of the rabbit PP and appen-
dix follicle, Waksman et al. [27] have suggested that cells
entering the follicle from the dome are induced to prolif-
erate once they arrive there.
Peyer’s Patches as a Source of IgA Precursor
Cells
In a previous section, evidence has been presented
which shows that IgA plasma cells in the intestine origi-
nate from IgA blast cells present in lymph draining from
the intestine. There is evidence to suggest that many of
these cells are produced in PP [127, 128]. It is generally
accepted that, after antigenic stimulation in the PP, IgA+
lymphoblasts (B220+IgA+) migrate through the lymph
and blood circulation, and eventually home to the LP of
the intestine. Craig and Cebra [91] transferred cells ob-
tained from different lymphoid organs into allogeneic
rabbits, which had been lethally irradiated. The cells of
donor origin had an allotypic marker (B4) on the light
chain of the sIg, which could be detected by immunofluo-
rescence techniques. These experiments showed that cells
obtained from the popliteal lymph nodes mostly gave rise
to IgG specific plasma cells in the spleen, but cells from
PP repopulated the LP of the intestine with IgA plasma
cells. This observation has since been confirmed in exper-
iments in which rabbits were given autologous PP cells
intravenously [129]. Cells obtained from rabbit PP have
also been shown to migrate to the mucosa of the respirato-
ry tract and differentiate into IgA plasma cells. The respi-
ratory tract contains lymphoid follicles, termed BALT
with many similar characteristics to PP [130, 131]. Rud-
zik et al. [129] have shown that cells from these areas also
have the ability to repopulate the LP of the gut and respi-
ratory tract when injected intravenously. The migration
of cells from the organised lymphoid tissue of one muco-
sal surface to other mucosal surfaces in the body may be
an important mechanism for disseminating immune re-
sponsiveness or nonresponsiveness (tolerance) and forms
the basis for the common mucosal immune system [86,
130–134]. Tolerance represents the most common and
important response of the host to environmental antigens,
including food and comensal bacterial components, for
the maintenance of an appropriate immunological ho-
meostasis. In order to examine whether PP could play an
important role for the maintenance of oral tolerance, Fuji-
hashi and co-workers [15, 16] found that PP-null mice
retained their capability to produce sIgA antibodies but
64 Pathobiology 2002–03;70:55–68
did not develop normal oral tolerance to protein antigens.
However, in a recent study, Yamamoto and colleagues
[135] showed that PP are not a strict requirement for
induction of mucosal IgA antibody responses in the gas-
trointestinal tract, suggesting an alternative mucosal im-
mune system. By immunohistochemistry, the authors
showed that PP-null mice possessed significant numbers
of IgA+ plasma cells in the LP and that oral immunization
of the PP null mice with OVA plus cholera toxin as a
mucosal adjuvant resulted in antigen specific mucosal IgA
and serum IgG antibody responses.
Role of Peyer’s Patch Cells in Immunoglobulin
Isotype Regulation
There is still a controversy regarding the role of antigen
in initiating these events [136]. However, as IgA plasma
cells are much reduced in the gut of germ free animals
[137], it seems likely that intestinal antigens are necessary
to induce precursor cells in PP to differentiate into IgA
plasma cells. Schaffner et al. [138, 139] have suggested
that in birds the bursa of Fabricius may be the major site
where contact occurs between lymphoid cells and the anti-
gens in the lumen of the intestine. As cells migrate from
the bursa at an early stage of differentiation this would
account for the observation that cells in the bursa produce
little detectable antibody [138, 139]. Evidence presented
in previous sections suggests that the same situation may
hold true for PP. The main difference between the bursa
and PP seems to be that while the bursa is the source of B
cells, which develop into plasma cells specific for each
class of Ig [reviewed in 138, 139], the cells from PP are
precursors predominantly of the IgA-specific plasma cells
[91, 104].
The role of T cells in immunoglobulin isotype regula-
tion is still unclear. Since the time it was recognised that T
cells play a role in B cell isotype differentiation [140, 141],
identification of the site of T cell action within the B cell
differentiation pathway has been the goal of research in
many laboratories. Kawanishi et al. [142] established that
T cell clones derived from PP, but not from spleen func-
tion as class specific switch cells, which induce B cell dif-
ferentiation to sIgA+ B cells. Evidence that T cells regulate
isotype differentiation at the level of naı̈ve murine B cells
comes from several sources. Kawanishi et al. [143, 144]
demonstrated that sIgM+sIgA – B cells could be induced to
switch sIgA+ B cells in the presence of T cell clones
derived from GALT. These sIgA+ B cells could then be
induced to secrete IgA in the presence of additional exoge-
Makala/Suzuki/Nagasawa
nous lymphokine [142]. Isakson et al. [145] showed that
murine sIgM+sIgG – B cells could be induced to secrete
IgG1 rather than IgG3 when stimulated by LPS in the
presence of the T cell derived factor IL-4 [146]. In the
human, Mayer et al. [147] demonstrated that sIgM+sIgG –
B cells could be induced to differentiate into IgG and IgA
secreting B cells in the presence of T cells derived from a
patient with Sezary syndrome. In a recent study, Fagaras-
an et al. [127, 128] showed that culturing LP and PP IgM+
B cells together with stromal cells enhances preferential
switching and differentiation of B cells to IgA+ plasma
cells, suggesting that IgA+ cells in the gut are generated in
situ from B220+IgM+ lymphocytes. These reports suggest
that switch and expansion of isotype-committed B cells
are regulated by separate T cell populations.
There is compelling evidence that T cells act during
isotype differentiation by preferentially expanding a pre-
committed B cell pool. Kiyono et al. [148, 149] and Mayer
et al. [150, 151] found that murine antigen-specific T cell
clones derive from PP specifically expanded sIgA+ B cells
but not sIgA – B cells via an IgA-binding factor. Benson
and Strobber [152] addressed the question of T cell regu-
lation of B cell isotype differentiation by using a non-neo-
plastic human tissue source. T cell clones were generated
from lymphoid follicles in normal appendiceal tissue. It
was established that individual T cell clones could act on
uncommitted sIgM+sIgG – B cells as well as IgA, thus
bringing about both switch and expansion of sIgA+ B cells.
In the IgE system. Ishizaka [153] and Nutman et al. [154]
detected T cell factors with Ig-binding properties that
selectively enhanced the differentiation of sIgE+ B cells.
Recently, Gardby and Lycke et al. [155] in a series of ex
vivo experiments revealed that CD19-deficient mice ex-
hibited poor responsiveness to oral immunization despite
evidence of unaltered total IgA level, germinal centres and
IgA-isotype switching in PP, thus providing compelling
evidence for the differential regulation of serum and
mucosal IgA immunity. Taken together, the evidence
from all the cited data suggests that T cells can act on B
cells to cause both switch of uncommitted B cells as well
as differential expansion of isotype-committed B cells and
that the PP provides a structural environment which per-
mits the productive interactions between T cell subsets
and sIg+ B cells to take place.
Acknowledgements
We are indebted to the Japanese Society for the Promotion of
Science (JSPS) for financial support. The first author is supported by
a research fellowship from JSPS for young scientists. This work was
also supported by grants from the Ministry of Education, Science,
Sports and Culture.

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