Originally published online as doi:10.1189/jlb.0307144 on June 12, 2007
Published online before print June 12, 2007
(Journal of Leukocyte Biology. 2007;82:795-800.)
© 2007
by Society for Leukocyte Biology
The impact of cell-bound antigen transport on mucosal tolerance induction
Oliver Pabst1,
Günter Bernhardt and
Reinhold Förster
Institute of Immunology, Hannover Medical School, Hannover, Germany
1 Correspondence: Institute of Immunology, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany. E-mail: pabst.oliver{at}mh-hannover.de
ABSTRACT
Mucosal surfaces are exposed continuously to a flood of foreign
antigens demanding a tightly controlled balance between immunity
and tolerance induction. Tolerance toward food and inhaled antigens,
known as oral and respiratory tolerance, respectively, evokes
a body-wide nonresponsiveness against the plethora of environmental
antigens. Key issues in understanding the induction of mucosal
tolerance relate to the site of antigen entrance, the mechanisms
of antigen transport, and the exact anatomical location where
lymphocytes meet their cognate antigens. In this regard, opposing
ideas have been put forward: In one scenario, antigens taken
up at mucosal surfaces are considered to spread throughout the
body, thus potentially evoking tolerogenic immune responses
in all secondary lymphoid organs. Alternatively, tolerance induction
might be confined to the draining regional lymph nodes (LN).
Recent observations strongly supported the latter scenario,
emphasizing the importance of regional LN and their network
of afferent lymphatics in this process. In this model, air-borne
and intestinal antigens are captured at mucosal sites by dendritic
cells, which then migrate exclusively in a CCR7-dependent way
to draining regional LN. Tolerance is then induced actively
by the activation of antigen-specific T cells, which are subsequently
deleted, become anergic, or alternatively, differentiate into
regulatory T cells. Thus, the concept of local induction of
immune responses seems to hold true for the majority of immune
reactions, regardless of whether they are tolerogenic or defensive
in their outcome.
Key Words: oral tolerance • CCR7 • intestine • lung • antigen presentation
A NEED FOR TOLERANCE
Throughout life, lymphocytes are generated continuously from
precursor cells in the primary lymphoid organs, which in mice
and humans, are the thymus and the bone marrow. A key feature
of this process is the generation of a highly diverse antigen
receptor repertoire, which allows recognizing a theoretically
unlimited array of antigens and builds the basis for the function
of the adaptive immune system. A particular drawback of this
system generating "random" antigen specificities is that a significant
fraction of these cells recognizes innocuous antigens and has
the potential to cause destructive immune responses. To avoid
such unwanted immune responses, two major principles of tolerance
evolved, which are known as central and peripheral tolerance.
Central tolerance acts in the primary lymphoid organs by deletion
of lymphocytes reacting strongly with self-antigens before such
cells are released into the periphery. However, the premises
underlying central tolerance require the presentation of the
respective antigens to the developing, immature lymphocytes
and thus, can only act on antigens actually present in the thymus
and in the bone marrow [
1
,
2
]. Although mechanisms such as
the autoimmune regulator-driven gene expression exist to warrant
the presence of a widespread array of self-antigens in the thymus,
a significant portion of them is missing. It is more important
that exogenous, nonself proteins escape this process of central
tolerance induction [
3
]. A particularly intimate contact with
exogenous antigens, which are not expressed in the thymus, is
a trademark of the mucosal surfaces. The physiological function
of these mucosal surfaces necessitates a thin and permeable
barrier, which allows, in particular, the exchange of gas and
food antigens, fueling the body's demand for energy. Thus, in
contrast with the rigid, multilayered skin epithelia protecting
the organism's outer surface in the nasopharyngeal, respiratory,
and gastrointestinal tract, only a single cell layer separates
the body's mostly sterile interior from an astonishing flora
of microorganisms and environmental antigens. The distinction
between innocuous and dangerous material imposes a tremendous
task to the mucosal immune system: Protective immune responses
must be raised toward harmful antigens, whereas innocuous antigens
and commensal bacteria need to be tolerated. Comparing the frequency
of innocuous and harmful antigens, it is evident that tolerance
induction is by far the more frequent reaction of the mucosal
immune system compared with protective immune responses. Failure
to establish tolerance to innocuous antigens can lead to severe
pathology. This is illustrated by inflammatory responses toward
the food protein gluten in celiac disease, to commensal bacteria
in Crohn's disease patients, and to inhaled antigen such as
pollen or industrial dust in allergic airway diseases. Thus,
understanding the establishment and maintenance of mucosal tolerance
is one of the key issues in mucosal immunology.
MECHANISMS OF ORAL TOLERANCE
Mucosal tolerance is best studied in the intestinal immune system.
The phenomenon of tolerance establishment to food antigens is
known as oral tolerance [
4
]. It is important that once established,
the effects of oral tolerance are not limited to the intestine
but act body-wide, actively inhibiting cellular and humoral
immune responses. Depending on the amount of antigen applied,
different mechanisms of tolerance induction to ingested antigens
have been identified in animal models. Low doses of antigen
have been suggested to act primarily by inducing regulatory
T cells (Tregs), whereas high doses of antigen have been shown
to cause cell depletion by apoptosis and/or anergy of antigen-specific
T cells [
5
]. However, irrespective of the type of ensuing T
cell reaction, antigen encounter by naïve, antigen-specific
T cells necessarily precedes and initiates oral tolerance induction.
The most important APC under immunogenic as well as tolerogenic conditions are dendritic cells (DC), which when conferring peripheral tolerance, are frequently referred to as "semi-mature" DC. These cells express intermediate or low levels of costimulatory molecules including CD80, CD86, and CD40, albeit showing high expression of MHC II. Semi-mature DC are thought to sample antigens continuously in peripheral tissues and traffic to draining lymph nodes (LN) in the absence of any inflammatory stimulation [6
7
8
9
], thereby delivering information about antigens present in peripheral tissues into the draining LN. Within the draining LN, semi-mature DC present their processed antigens to naïve T cells. It is notable that interaction of T cells recognizing their cognate antigen presented by semi-mature DC is believed to result in T cell proliferation. However, in contrast to T cells primed under immunogenic conditions, T cells induced by semi-mature DC will undergo abortive proliferation, resulting in the deletion of these cells, or differentiate into anergic cells or Tregs [10
].
ACTIVE MECHANISMS OF ANTIGEN UPTAKE IN THE INTESTINE
Active sampling of intestinal antigens is achieved by at least
two fundamentally different, cell-dependent mechanisms: uptake
of luminal antigens by specialized microfold (M) cells or by
DC localized in the intestinal lamina propria [
11
12
13
] (
Fig. 1
).
Although M cells have been observed in intestinal villi [
14
],
the vast majority of them gathers within the specialized epithelia
overlying intestinal follicles. In particular, these intestinal
follicles include Peyer's patches (PP), which are huge, aggregated
lymphoid follicles aligned along the antimesenteric axis of
the small intestine [
15
]. In addition, numerous, much smaller
intestinal lymphoid follicles, which we named solitary intestinal
lymphoid tissue, decorate the entire small intestine [
16
].
Solitary intestinal lymphoid tissue adapts in response to microbial
stimulation to a phenotype reminiscent of a single-domed PP,
including a M cell-containing, follicle-associated epithelium
[
17
]. Numerous studies have addressed the role of PP for oral
tolerance induction. The major body of evidence in the field
suggests that PP seem to be dispensable for oral tolerance induction
[
4
,
18
,
19
]. Oral tolerance cannot be induced in lymphotoxin
-deficient mice, which lack all secondary lymphoid organs, except
the spleen. However, reconstitution of only the MLN in these
mice suffices to regain the capability to induce oral tolerance,
indicating that the simultaneous lack of PP and solitary intestinal
lymphoid tissue does not impair oral tolerance induction per
se [
20
]. Taken together, these findings suggest that M cell-mediated
antigen uptake and intestinal follicles might not be central
for the induction of tolerance in the intestine.
In addition to M cells, lamina propria DC are considered to
sample intestinal antigens constitutively. These DC are capable
in extending dendrites through the epithelium, which end up
as bulb-shaped structures, residing in the intestinal lumen
[
21
,
22
]. Recently, these extensions were shown to be induced
by TLR signaling and to actively engulf noninvasive
Salmonella [
23
]. Although the functional relevance of such intraepithelial
dendrites is not yet clear and might vary between different
parts of the small intestine and different mouse strains [
24
],
lamina propria DC appear strikingly well-suited to confer oral
tolerance. The first important evidence, that DC indeed mediate
oral tolerance in vivo, came from studying oral tolerance in
fms-like tyrosine kinase 3 ligand-treated mice. This treatment
amplifies the number of DC present in virtually all organs.
In these mice, oral tolerance could be induced with antigen
doses, which were ineffective in unmanipulated mice [
25
]. This
indicates that the expansion of the DC pool boosts the capacity
to induce oral tolerance.
Moreover, in the intestinal immune system, DC constitutively traffic from the intestine and PP to the draining MLN. This suggests that similar to the situation in skin-draining LN, DC constantly deliver information about antigens present in the periphery/intestine into the draining LN [26
]. Indeed, the majority of lamina propria DC phenotypically resembles semimature DC described in peripheral LN [27
28
29
], further supporting the idea that lamina propria DC might confer oral tolerance induction. It is notable that these observations do not necessarily imply that intraepithelial extensions are mandatory for DC function. Instead, DC might as well take up antigen locally in the lamina propria. Such a process might be predominantly amendable to the uptake and DC-mediated transport of soluble nutrients absorbed by the intestinal epithelium as well as intestinal tissue-derived antigens, e.g., apoptotic enterocytes. In parallel, active sampling via transepithelial dendritic extensions might be more relevant for monitoring intestinal flora.
PASSIVE DISSEMINATION OF ANTIGEN
Although proteolytic and chemical cleavage in the stomach and
small intestine degrades the majority of food proteins to shorter
fragments or even free amino acids, thereby losing immunogenicity,
a variable fraction of food protein may reach the circulation
intact or in the form of polypeptides, which can be recognized
and/or presented by immune cells [
30
31
32
33
]. Particularly
high concentrations of such blood-borne food antigens reach
the liver, which via the portal vein, directly receives blood
rich in food antigen. Injection of antigen directly into the
portal vein has been shown to induce systemic tolerance, indicating
that this route of antigen encounter might confer tolerance
induction to intestinal antigens [
34
]. Along this line, redirecting
the antigen-rich blood of the portal vein away from the liver
by surgery has been shown to impair oral tolerance induction,
further substantiating the tolerogenic potential of the liver
[
35
]. Uptake of antigens from the blood might be achieved by
liver sinusoidal endothelial cells (LSEC), which express high
amounts of scavenger receptors. In addition, LSEC are able to
present antigens to naïve CD4 T cells as well as to cross-present
them to CD8 T cells, indicating that these cells might contribute
directly to the induction of oral tolerance [
36
,
37
]. Alternatively,
liver resident DC might take over delivery of the antigen and
present food antigens in the liver-draining LN.
Moreover, several reports suggested that food antigens reaching peripheral LN and spleen via the blood circulation could lead to productive antigen presentation. Indeed, antibodies specific for distinct MHC II complexes loaded with food peptides recognized corresponding DC within minutes after feeding those antigens. This emphasizes that after their uptake, such peptides distribute rapidly throughout the body. In favor of such a scenario, similar kinetics for the induction of T cell proliferation was observed in PP and gut-draining MLN compared with skin-draining LN and spleen [38
, 39
]. Moreover, in vivo microscopy revealed a clustering behavior of antigen-specific T cells with APC in the gut-draining MLN and distant peripheral LN as early as 8 h after oral antigen application [40
].
In contrast to these observations, other studies, including our own work, reported that proliferating T cells accumulate first in gut-associated lymphoid tissue (GALT) and MLN and only with delayed kinetics in peripheral LN and spleen [41
42
43
44
]. Consequently, immunological handling of food antigens might be restricted to the intestinal immune system, and the subsequent appearance of dividing, antigen-specific T cells at distant sites most likely reflects the seeding of locally activated cells to nondraining LN and spleen. As T cells might already enter the periphery immediately following their activation in the intestinal immune system, thus disseminating in the body rapidly, the comparison of T cell kinetics in different lymphoid compartments might be insufficient to discriminate between both scenarios. We reported recently direct evidence for the exclusive activation of T cells in the intestinal immune system by using the immunomodulatory drug FTY720. Treatment of mice with FTY720 inhibits the recirculation of lymphocytes by specifically blocking their egress into efferent lymphatics [45
] and leaving the free dissemination of soluble antigen untouched. In consequence, FTY720 causes blood lymphopenia and traps lymphocytes in the LN. It is striking that following oral antigen administration, dividing antigen-specific T cells were missing completely in peripheral LN and spleen of mice, which received FTY720 continuously. In contrast, no differences were apparent in PP and MLN of FTY720-treated compared with untreated mice with regard to activation of T cells specifically recognizing orally applied antigens [41
]. This important observation was confirmed recently by another report [46
]. Thus, proliferated T cells present in peripheral LN and spleen after oral antigen feeding most likely have seeded peripheral lymphoid organs after the initial antigen encounter in the intestinal immune system. It is more important that these observations reveal a fundamental aspect of GALT and MLN, as they seem privileged in the induction of T cell responses upon oral antigen application. In contrast, distant LN cannot instruct T cells accordingly, despite the free access of antigen to their DC network.
REGIONAL LN ARE ESSENTIAL FOR TOLERANCE INDUCTION
Anticipating that immunologically relevant presentation of food
antigens is restricted to the intestinal immune system, it would
indeed be expected that other lymphoid organs such as peripheral
LN should not be able to compensate for the lack of GALT and/or
MLN. In line with this idea, we reported recently that surgical
removal of the MLN from wild-type mice impairs oral tolerance
induction [
41
]. Moreover, as already mentioned above, reconstitution
of only the MLN in lymphotoxin
-deficient mice, which lack all
LN and PP, is sufficient to regain the ability to induce oral
tolerance in these animals [
20
]. Such dependency of the regional
LN for tolerance induction is not limited to the intestinal
immune system, as adenectomy of nose-draining LN completely
blocked the capacity to induce mucosal tolerance by intranasal
antigen application [
47
]. Together, these observations demonstrate
that the regional LN draining the antigen-challenged site are
necessary and sufficient for mucosal tolerance induction (for
a recent review, see ref. [
48
]).
Within the regional LN, LN resident DC and/or DC, which emigrated recently from the mucosal surfaces, might be critical for mucosal tolerance induction. LN resident DC would need to acquire the antigen locally in the LN from blood or from afferent lymph. Applying transplantation of the small bowel together with its draining MLN, we were able to demonstrate that antigen transport via the circulation is not sufficient to induce proliferation of antigen-specific T cells. This held true, not only for peripheral LN and spleen but also for grafted MLN, which were connected to the blood circulation of the host, which, however, did not receive afferent lymph drained from the antigen-challenged small intestine of the host [41
]. Thus, these observations provide direct, experimental proof for the intuitive view that first of all, the supply with afferent lymph distinguishes the MLN from other peripheral LN as the primary sites for oral tolerance induction.
LESSONS FROM STUDYING MUCOSAL TOLERANCE IN CCR7-DEFICIENT MICE
The apparent dependence on intact, afferent lymphatics in the
proper function of MLN in tolerance induction may indicate that
antigen delivery via lymphatics might be cell-bound, i.e., carried
out by antigen-loaded DC. In this respect, it was a striking
observation that oral tolerance as well as tolerance to inhaled
antigen could not be induced in mice deficient for the chemokine
receptor CCR7 [
41
,
49
], which is essentially required for
the migration of DC from the skin, gut, and lung into the respective
draining LN [
29
,
41
,
49
,
50
]. In contrast, CCR7 deficiency
did not affect the proliferation of antigen-specific T cells
in these LN after systemic antigen administration [
29
,
41
],
suggesting that impaired DC migration might account for the
lack of tolerance induction observed in these mice.
In agreement with the impaired tolerance induction in CCR7-deficient mice, antigen-specific T cells carrying the intact CCR7 receptor and thus, competent to enter draining LN, failed to proliferate after adoptive transfer in CCR7-deficient recipients and subsequent antigen exposure via the gut or the lung [41
, 49
]. These observations argue for an essential role of the CCR7-dependent transport of antigen by DC from the antigen-challenged mucosa into the draining LN for the induction of tolerogenic-immune responses. This model, of course, does not rule out passive antigen transport per se but merely respects the obvious lack of immune reactivity in the draining LN of CCR7-deficient mice after antigen challenge under tolerogenic conditions. Indeed, we observed that fluorescently labeled antigen given intratracheally reached the draining bronchial LN as early as 30 min after application in wild-type and CCR7-deficient mice [49
]. Moreover, almost half of all LN resident DC displayed a detectable fluorescent signal, indicating that the antigen not only arrived in sufficient quantities in the LN but was also taken up by DC. However, when antigen-carrying DC were sorted from the lung-draining LN 30 min after intratracheal antigen transfer, these DC were unable to stimulate proliferation of antigen-specific T cells in vitro. In contrast, if the same experiment were performed 1 day after antigen delivery, sorted DC were capable of inducing T cell proliferation [49
]. These observations imply that induction of T cell proliferation in response to antigen application performed under tolerogenic conditions requires the active delivery of antigens by DC migrating from the periphery into the draining LN. In contrast, antigen, which reaches the LN passively via lymph or blood, does not result in T cell proliferation, although such antigen might be detectable on LN resident DC.
TO BE TOLEROGENIC—A NEW MODEL FOR MUCOSAL TOLERANCE INDUCTION
The most puzzling implication of this hypothesis is that the
uptake of antigen by LN resident DC remains immunologically
inconspicuous. However, migration of tissue resident DC under
immunogenic as well as tolerogenic conditions is accompanied
with profoundly changed properties of these cells, most evidently,
by the regulation of costimulatory molecules. Therefore, DC
entering the LN from the periphery are phenotypically different
from immature DC resident in the LN [
51
]. Thus, although LN
resident DC might take up passively drained antigen locally
in the LN, this process might be insufficient to stimulate T
cell responses in the absence of additional regulatory signals.
In a well-recognized work, Itano and colleagues [52
] demonstrated that antigen arrives in skin-draining LN in two waves. In a first wave, antigen reaches the LN by rapid diffusion after s.c. injection, which is comparable with the scenario already described above for inhaled antigen. This first wave resulted in antigen-derived peptide presentation by LN resident DC. It is surprising, however, that this first-wave antigen was sufficient to stimulate T cell proliferation. A second wave of antigen was carried into the skin-draining LN in a pertussin toxin-sensitive manner 24 h after antigen injection. This second wave of antigen likewise induced T cell stimulation. However, only the second and not the first wave of antigen induced delayed-type hypersensitivity reactions [52
], indicating that the type of ensuing immune reaction depends on the mode of antigen delivery into the LN.
At first glance, these observations appear to be inconsistent with our hypothesis, which postulates that antigens access the draining LN rapidly following application, i.e., in the first wave, remain immunologically, entirely inconspicuous and do not stimulate any T cell activity. Upon closer inspection, important differences in the distinct, experimental setups used may help explain the discrepancies between the complete lack of immune reactivity upon oral antigen application in CCR7-deficient mice and the induction of T cell proliferation in response to the first wave of antigen reaching the draining LN, reported by Itano et al. [52
]. Whereas oral-feeding and inhalation of antigen definitively do not provide any inflammatory stimuli, s.c. injection is always accompanied with tissue injury. Such injury, even if limited in its severity, might be sufficient to convert a tolerogenic response into an inflammatory response. This is even more obvious when considering that to separate first- and second-wave effects of antigen delivery, Itano and colleagues [52
] physically removed the antigen-injected site by amputation. Therefore, in addition to antigen being passively drained, inflammatory cytokines will probably reach the draining LN following such procedures. Thus, it seems likely that these cytokines will enable LN resident DC carrying the first-wave antigen to initiate T cell responses. Moreover, it should be considered that in contrast to the gut-associated lymphoid tissue, the lymphoid system surveying the skin is by nature not designed to handle a large liquid input carrying antigen from outside the body. Therefore, the experimental setup selected by Itano et al. [52
] may be less-suited to draw conclusions about the tolerance phenomena discussed here. As outlined above, an invasion through the skin is almost inevitably correlated with injury, whereas the immune system is well-advised to "interpret" such an event differently compared with the routine uptake of environmental antigens across the intestinal epithelia. At the end, this represents just another aspect of the regional lymphoid compartments, which are trained evolutionary to consider the divergent circumstances of antigen entry into the body for the sake of a sane balance between tolerance and adaptive immune responses. Therefore, it is advantageous for the organism that tolerance and protective immune responses originate in the regional lymphoid compartments draining the affected tissue. This verdict decided locally is then communicated throughout the body by disseminating T cells instead of being initialized de novo in any remote lymphoid organ.
In summary, we suggest that the antigen reaches draining LN via the lymphatic system in two distinct waves. In a first wave, antigen is drained passively into the LN and then is taken up and processed by DC and subsequently presented on the surface of these LN resident DC. However, this process will not necessarily induce immune responses, and in the absence of additional stimulatory signals, presentation of first-wave antigen remains immunologically silent. In contrast, this passive antigen transport might suffice to raise protective immune responses in cooperation with additional inflammatory stimuli. At later time-points, antigen will be carried to the LN by active transport via DC. This process is sensitive to pertussis toxin and depends on CCR7. Antigen transport by these migratory DC is essentially required for the induction of tolerogenic-immune responses. Thus, the central role of CCR7 as well as the importance of regional LN for tolerance induction can be tracked back to the need of DC-mediated antigen transport to induce tolerance at mucosal surfaces.
ACKNOWLEDGEMENTS
This work was supported by Deutsche Forschungsgemeinschaft Grants
SFB621-A1 and SFB587-B3 to R. F. We thank Tim Worbs and Sabrina
Dähne for critically reading the manuscript.
Received March 9, 2007;
revised May 11, 2007;
accepted May 17, 2007.
REFERENCES
1 - Kyewski, B., Klein, L. (2006) A central role for central tolerance Annu. Rev. Immunol. 24,571-606[CrossRef][Medline]
2 - Goodnow, C. C., Sprent, J., Fazekas de St Groth, B., Vinuesa, C. G. (2005) Cellular and genetic mechanisms of self tolerance and autoimmunity Nature 435,590-597[CrossRef][Medline]
3 - Goldrath, A. W., Hedrick, S. M. (2005) Central tolerance matters Immunity 23,113-114[CrossRef][Medline]
4 - Mowat, A. M. (2003) Anatomical basis of tolerance and immunity to intestinal antigens Nat. Rev. Immunol. 3,331-341[CrossRef][Medline]
5 - Faria, A. M., Weiner, H. L. (2005) Oral tolerance Immunol. Rev. 206,232-259[CrossRef][Medline]
6 - Hawiger, D., Inaba, K., Dorsett, Y., Guo, M., Mahnke, K., Rivera, M., Ravetch, J. V., Steinman, R. M., Nussenzweig, M. C. (2001) Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo J. Exp. Med. 194,769-779[Abstract/Free Full Text]
7 - Steinman, R. M., Hawiger, D., Liu, K., Bonifaz, L., Bonnyay, D., Mahnke, K., Iyoda, T., Ravetch, J., Dhodapkar, M., Inaba, K., Nussenzweig, M. (2003) Dendritic cell function in vivo during the steady state: a role in peripheral tolerance Ann. N. Y. Acad. Sci. 987,15-25[CrossRef][Medline]
8 - Steinman, R. M., Hawiger, D., Nussenzweig, M. C. (2003) Tolerogenic dendritic cells Annu. Rev. Immunol. 21,685-711[CrossRef][Medline]
9 - Rutella, S., Danese, S., Leone, G. (2006) Tolerogenic dendritic cells: cytokine modulation comes of age Blood 108,1435-1440[Abstract/Free Full Text]
10 - Guermonprez, P., Valladeau, J., Zitvogel, L., Thery, C., Amigorena, S. (2002) Antigen presentation and T cell stimulation by dendritic cells Annu. Rev. Immunol. 20,621-667[CrossRef][Medline]
11 - Niess, J. H., Reinecker, H. C. (2006) Dendritic cells in the recognition of intestinal microbiota Cell. Microbiol. 8,558-564[CrossRef][Medline]
12 - Hooper, L. V., Gordon, J. I. (2001) Commensal host-bacterial relationships in the gut Science 292,1115-1118[Abstract/Free Full Text]
13 - Niedergang, F., Kweon, M. N. (2005) New trends in antigen uptake in the gut mucosa Trends Microbiol. 13,485-490[CrossRef][Medline]
14 - Jang, M. H., Kweon, M. N., Iwatani, K., Yamamoto, M., Terahara, K., Sasakawa, C., Suzuki, T., Nochi, T., Yokota, Y., Rennert, P. D., Hiroi, T., Tamagawa, H., Iijima, H., Kunisawa, J., Yuki, Y., Kiyono, H. (2004) Intestinal villous M cells: an antigen entry site in the mucosal epithelium Proc. Natl. Acad. Sci. USA 101,6110-6115[Abstract/Free Full Text]
15 - Neutra, M. R., Mantis, N. J., Kraehenbuhl, J. P. (2001) Collaboration of epithelial cells with organized mucosal lymphoid tissues Nat. Immunol. 2,1004-1009[CrossRef][Medline]
16 - Pabst, O., Herbrand, H., Worbs, T., Friedrichsen, M., Yan, S., Hoffmann, M. W., Korner, H., Bernhardt, G., Pabst, R., Forster, R. (2005) Cryptopatches and isolated lymphoid follicles: dynamic lymphoid tissues dispensable for the generation of intraepithelial lymphocytes Eur. J. Immunol. 35,98-107[CrossRef][Medline]
17 - Pabst, O., Herbrand, H., Friedrichsen, M., Velaga, S., Dorsch, M., Berhardt, G., Worbs, T., Macpherson, A. J., Forster, R. (2006) Adaptation of solitary intestinal lymphoid tissue in response to microbiota and chemokine receptor CCR7 signaling J. Immunol. 177,6824-6832[Abstract/Free Full Text]
18 - Kraus, T. A., Brimnes, J., Muong, C., Liu, J. H., Moran, T. M., Tappenden, K. A., Boros, P., Mayer, L. (2005) Induction of mucosal tolerance in Peyer's patch-deficient, ligated small bowel loops J. Clin. Invest. 115,2234-2243[CrossRef][Medline]
19 - Spahn, T. W., Fontana, A., Faria, A. M., Slavin, A. J., Eugster, H. P., Zhang, X., Koni, P. A., Ruddle, N. H., Flavell, R. A., Rennert, P. D., Weiner, H. L. (2001) Induction of oral tolerance to cellular immune responses in the absence of Peyer's patches Eur. J. Immunol. 31,1278-1287[CrossRef][Medline]
20 - Spahn, T. W., Weiner, H. L., Rennert, P. D., Lugering, N., Fontana, A., Domschke, W., Kucharzik, T. (2002) Mesenteric lymph nodes are critical for the induction of high-dose oral tolerance in the absence of Peyer's patches Eur. J. Immunol. 32,1109-1113[CrossRef][Medline]
21 - Rescigno, M., Urbano, M., Valzasina, B., Francolini, M., Rotta, G., Bonasio, R., Granucci, F., Kraehenbuhl, J. P., Ricciardi-Castagnoli, P. (2001) Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria Nat. Immunol. 2,361-367[CrossRef][Medline]
22 - Niess, J. H., Brand, S., Gu, X., Landsman, L., Jung, S., McCormick, B. A., Vyas, J. M., Boes, M., Ploegh, H. L., Fox, J. G., Littman, D. R., Reinecker, H. C. (2005) CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance Science 307,254-258[Abstract/Free Full Text]
23 - Chieppa, M., Rescigno, M., Huang, A. Y., Germain, R. N. (2006) Dynamic imaging of dendritic cell extension into the small bowel lumen in response to epithelial cell TLR engagement J. Exp. Med. 203,2841-2852[Abstract/Free Full Text]
24 - Vallon-Eberhard, A., Landsman, L., Yogev, N., Verrier, B., Jung, S. (2006) Transepithelial pathogen uptake into the small intestinal lamina propria J. Immunol. 176,2465-2469[Abstract/Free Full Text]
25 - Viney, J. L., Mowat, A. M., O'Malley, J. M., Williamson, E., Fanger, N. A. (1998) Expanding dendritic cells in vivo enhances the induction of oral tolerance J. Immunol. 160,5815-5825[Abstract/Free Full Text]
26 - Huang, F. P., Platt, N., Wykes, M., Major, J. R., Powell, T. J., Jenkins, C. D., MacPherson, G. G. (2000) A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes J. Exp. Med. 191,435-444[Abstract/Free Full Text]
27 - Lutz, M. B., Schuler, G. (2002) Immature, semi-mature and fully mature dendritic cells: which signals induce tolerance or immunity? Trends Immunol. 23,445-449[CrossRef][Medline]
28 - Johansson-Lindbom, B., Svensson, M., Pabst, O., Palmqvist, C., Marquez, G., Forster, R., Agace, W. W. (2005) Functional specialization of gut CD103+ dendritic cells in the regulation of tissue-selective T cell homing J. Exp. Med. 202,1063-1073[Abstract/Free Full Text]
29 - Ohl, L., Mohaupt, M., Czeloth, N., Hintzen, G., Kiafard, Z., Zwirner, J., Blankenstein, T., Henning, G., Forster, R. (2004) CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions Immunity 21,279-288[CrossRef][Medline]
30 - Warshaw, A. L., Walker, W. A., Isselbacher, K. J. (1974) Protein uptake by the intestine: evidence for absorption of intact macromolecules Gastroenterology 66,987-992[Medline]
31 - Husby, S., Jensenius, J. C., Svehag, S. E. (1985) Passage of undegraded dietary antigen into the blood of healthy adults. Quantification, estimation of size distribution, and relation of uptake to levels of specific antibodies Scand. J. Immunol. 22,83-92[CrossRef][Medline]
32 - Furrie, E., Smith, R. E., Turner, M. W., Strobel, S., Mowat, A. M. (2002) Induction of local innate immune responses and modulation of antigen uptake as mechanisms underlying the mucosal adjuvant properties of immune stimulating complexes (ISCOMS) Vaccine 20,2254-2262[CrossRef][Medline]
33 - Swarbrick, E. T., Stokes, C. R., Soothill, J. F. (1979) Absorption of antigens after oral immunization and the simultaneous induction of specific systemic tolerance Gut 20,121-125[Abstract/Free Full Text]
34 - Qian, J., Hashimoto, T., Fujiwara, H., Hamaoka, T. (1985) Studies on the induction of tolerance to alloantigens. I. The abrogation of potentials for delayed-type-hypersensitivity response to alloantigens by portal venous inoculation with allogeneic cells J. Immunol. 134,3656-3661[Abstract]
35 - Yang, R., Liu, Q., Grosfeld, J. L., Pescovitz, M. D. (1994) Intestinal venous drainage through the liver is a prerequisite for oral tolerance induction J. Pediatr. Surg. 29,1145-1148[CrossRef][Medline]
36 - Limmer, A., Ohl, J., Kurts, C., Ljunggren, H. G., Reiss, Y., Groettrup, M., Momburg, F., Arnold, B., Knolle, P. A. (2000) Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance Nat. Med. 6,1348-1354[CrossRef][Medline]
37 - Limmer, A., Ohl, J., Wingender, G., Berg, M., Jungerkes, F., Schumak, B., Djandji, D., Scholz, K., Klevenz, A., Hegenbarth, S., Momburg, F., Hammerling, G. J., Arnold, B., Knolle, P. A. (2005) Cross-presentation of oral antigens by liver sinusoidal endothelial cells leads to CD8 T cell tolerance Eur. J. Immunol. 35,2970-2981[CrossRef][Medline]
38 - Gutgemann, I., Fahrer, A. M., Altman, J. D., Davis, M. M., Chien, Y. H. (1998) Induction of rapid T cell activation and tolerance by systemic presentation of an orally administered antigen Immunity 8,667-673[CrossRef][Medline]
39 - Smith, K. M., Davidson, J. M., Garside, P. (2002) T-cell activation occurs simultaneously in local and peripheral lymphoid tissue following oral administration of a range of doses of immunogenic or tolerogenic antigen although tolerized T cells display a defect in cell division Immunology 106,144-158[CrossRef][Medline]
40 - Zinselmeyer, B. H., Dempster, J., Gurney, A. M., Wokosin, D., Miller, M., Ho, H., Millington, O. R., Smith, K. M., Rush, C. M., Parker, I., Cahalan, M., Brewer, J. M., Garside, P. (2005) In situ characterization of CD4+ T cell behavior in mucosal and systemic lymphoid tissues during the induction of oral priming and tolerance J. Exp. Med. 201,1815-1823[Abstract/Free Full Text]
41 - Worbs, T., Bode, U., Yan, S., Hoffmann, M. W., Hintzen, G., Bernhardt, G., Forster, R., Pabst, O. (2006) Oral tolerance originates in the intestinal immune system and relies on antigen carriage by dendritic cells J. Exp. Med. 203,519-527[Abstract/Free Full Text]
42 - Kunkel, D., Kirchhoff, D., Nishikawa, S., Radbruch, A., Scheffold, A. (2003) Visualization of peptide presentation following oral application of antigen in normal and Peyer's patches-deficient mice Eur. J. Immunol. 33,1292-1301[CrossRef][Medline]
43 - Blanas, E., Davey, G. M., Carbone, F. R., Heath, W. R. (2000) A bone marrow-derived APC in the gut-associated lymphoid tissue captures oral antigens and presents them to both CD4+ and CD8+ T cells J. Immunol. 164,2890-2896[Abstract/Free Full Text]
44 - Williamson, E., O'Malley, J. M., Viney, J. L. (1999) Visualizing the T-cell response elicited by oral administration of soluble protein antigen Immunology 97,565-572[CrossRef][Medline]
45 - Matloubian, M., Lo, C. G., Cinamon, G., Lesneski, M. J., Xu, Y., Brinkmann, V., Allende, M. L., Proia, R. L., Cyster, J. G. (2004) Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1 Nature 427,355-360[CrossRef][Medline]
46 - Lee, J. W., Epardaud, M., Sun, J., Becker, J. E., Cheng, A. C., Yonekura, A. R., Heath, J. K., Turley, S. J. (2007) Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self Nat. Immunol. 8,181-190[CrossRef][Medline]
47 - Wolvers, D. A., Coenen-de Roo, C. J., Mebius, R. E., van der Cammen, M. J., Tirion, F., Miltenburg, A. M., Kraal, G. (1999) Intranasally induced immunological tolerance is determined by characteristics of the draining lymph nodes: studies with OVA and human cartilage gp-39 J. Immunol. 162,1994-1998[Abstract/Free Full Text]
48 - Kraal, G., Samsom, J. N., Mebius, R. E. (2006) The importance of regional lymph nodes for mucosal tolerance Immunol. Rev. 213,119-130[CrossRef][Medline]
49 - Hintzen, G., Ohl, L., Del Rio, M. L., Rodriguez-Barbosa, J. I., Pabst, O., Kocks, J. R., Krege, J., Hardtke, S., Forster, R. (2006) Induction of tolerance to innocuous inhaled antigen relies on a CCR7-dependent dendritic cell-mediated antigen transport to the bronchial lymph node J. Immunol. 177,7346-7354[Abstract/Free Full Text]
50 - Jang, M. H., Sougawa, N., Tanaka, T., Hirata, T., Hiroi, T., Tohya, K., Guo, Z., Umemoto, E., Ebisuno, Y., Yang, B. G., Seoh, J. Y., Lipp, M., Kiyono, H., Miyasaka, M. (2006) CCR7 is critically important for migration of dendritic cells in intestinal lamina propria to mesenteric lymph nodes J. Immunol. 176,803-810[Abstract/Free Full Text]
51 - Wilson, N. S., El-Sukkari, D., Belz, G. T., Smith, C. M., Steptoe, R. J., Heath, W. R., Shortman, K., Villadangos, J. A. (2003) Most lymphoid organ dendritic cell types are phenotypically and functionally immature Blood 102,2187-2194[Abstract/Free Full Text]
52 - Itano, A. A., McSorley, S. J., Reinhardt, R. L., Ehst, B. D., Ingulli, E., Rudensky, A. Y., Jenkins, M. K. (2003) Distinct dendritic cell populations sequentially present antigen to CD4 T cells and stimulate different aspects of cell-mediated immunity Immunity 19,47-57[CrossRef][Medline]
This article has been cited by other articles:
|
|
|
|
 
S. I. Hammerschmidt, M. Ahrendt, U. Bode, B. Wahl, E. Kremmer, R. Forster, and O. Pabst
Stromal mesenteric lymph node cells are essential for the generation of gut-homing T cells in vivo
J. Exp. Med.,
October 27, 2008;
205(11):
2483 - 2490.
[Abstract]
[Full Text]
[PDF]
|
|
|
TOP
ABSTRACT
A NEED FOR TOLERANCE