Available online at www.sciencedirect.com
Endocytosis mechanisms and the cell biology of antigen
presentation
Sven Burgdorf and Christian Kurts
Recent evidence revealed that presentation of soluble antigens
is governed by the endocytosis mechanisms that determine the
intracellular routing of the endocytosed antigens. Soluble
antigens intended for classical exogenous MHC-II-restricted
presentation are internalized into lysosomes. Soluble antigens
destined for crosspresentation are taken up by distinct
endocytosis mechanisms and are conveyed into stable early
endosomes. Particulate antigens enter phagosomes, in which
both MHC-I-restricted and MHC-II-restricted presentation is
initiated. In this review, we discuss the mechanistical
differences in presentation of soluble and particulate antigen,
the correlation of various endocytic receptors with antigen
routing and presentation, the differential expression of these
receptors in antigen-presenting cell subsets with respect to
their ability to crosspresent, and implications on the molecular
mechanisms controlling cross-presentation.
Addresses
Institute of Molecular Medicine and Experimental Immunology
(IMMEI), Friedrich-Wilhelms-Universität, Bonn, Germany
Corresponding author: Kurts, Christian ([email protected])
Current Opinion in Immunology 2008, 20:89–95
This review comes from a themed issue on
Antigen Processing and Recognition
Edited by Emil Unanue and James McCluskey
Available online 30th January 2008
0952-7915 # 2007 Elsevier Ltd. Open access under CC BY-NC-ND license.
DOI 10.1016/j.coi.2007.12.002
Introduction
The traditional view of antigen presentation stated that
intracellularly synthesized antigens, for example of viral or
tumor origin, are presented by MHC I molecules and
activate CD8+ cytotoxic T cells, whereas extracellular
antigens are presented by professional antigen-presenting
cells (APCs) with MHC II molecules to CD4+ T helper
cells. To this end, extracellular antigens are internalized
into specialized organelles, which are termed phagosomes
in case of cell-associated antigens, and endosomes for soluble antigens. Both compartments subsequently mature and
undergo a series of molecular changes, such as acidification
and fusion with organelles containing degrading enzymes,
in particular lysosomes. In late endosomes/lysosomes, antigenic peptides can be generated and loaded onto MHC II
molecules, followed by transport of these complexes to the
cell surface for presentation to CD4+ T cells.
www.sciencedirect.com
Crosspresentation denotes the MHC-I-restricted
presentation of extracellular antigens. The existence of
this process has long been controversial, though the
necessity of professional APCs for activation also of
CD8+ T cells clearly implies the requirement of crosspresentation for immunity against viruses that do not
infect APCs, or against tumors derived from non-APCs.
Before substantial evidence for crosspresentation had
become available, the assumption that extracellular antigen was presented exclusively to CD4+ T cells had
implied that the different mechanisms of endocytosis
(phagocytosis for particulate antigens, receptor-mediated
endocytosis and pinocytosis for soluble antigens) supplied
only MHC-II-restricted antigen presentation. Thus, a
differential influence of these mechanisms on antigen
presentation, in particular on crosspresentation, had not
been an obvious question to be experimentally addressed.
Here, we discuss associations between endocytosis receptors, target organelles, DC subtypes, and T cell activation
that shed new light on the mechanisms governing antigen
presentation.
Presentation of particulate antigens is
time-dependent
Particulate antigens are internalized into phagosomes,
from where processing for presentation on MHC I and
MHC II molecules is initiated. Recent studies have
demonstrated that active alkalization of the phagosome
by the NADPH oxidase NOX2 is required for crosspresentation [1]. This alkalization prevented activation of
lysosomal proteases, so that internalized particulate antigens were rescued from rapid degradation and remained
available for loading onto MHC I [2]. Such crosspresentation involved export from the phagosome into the cytoplasm for proteasomal processing [3], and TAP-dependent
import of resulting peptides into the compartment where
they are loaded onto MHC I molecules, which has been
proposed to be the same phagosome [4–6].
However, active alkalization of phagosomes was transient. After some time when antigens could be processed
for crosspresentation, ROS production ceased, resulting
in phagosome acidification and activation of lysosomal
proteases [7]. This permitted generation of peptides from
particulate antigens within the phagosome, which then
could be loaded onto MHC II molecules [8]. Hence,
MHC-I-restricted and MHC-II-restricted presentation
of particulate antigens occur sequentially: first, crosspresentation occurs at mildly acidic intraphagosomal pH,
followed by loading onto MHC II molecules at more
acidic pH (Figure 1).
Current Opinion in Immunology 2008, 20:89–95
90 Antigen Processing and Recognition
Figure 1
Crosspresentation of particulate antigen is time-dependent, whereas crosspresentation of soluble antigens is localization-dependent. Particulate
antigens are taken up by phagocytosis. Transient alkalization of the phagosome prevents lysosomal antigen degradation and allows
crosspresentation. After acidification, lysosomal proteases are activated and process antigens for presentation on MHC II molecules. Soluble
antigens intended for crosspresentation are internalized into stable early endosomes, whereas those aimed at classical MHC-II-restricted
presentation are taken up by distinct endocytosis mechanisms and are routed into lysosomes.
Presentation of soluble antigens is
localization-dependent
Presentation of soluble antigens is assumed to be regulated
by mechanisms similar to those governing presentation of
particulate antigens. Consequently, soluble antigens are
thought to be targeted toward a common pool of endosomes, which matured toward late endosomes and fused
with lysosomes, in which peptides for MHC-II-restricted
presentation can be generated [8]. Antigens intended for
crosspresentation consequently would have to be diverted
from endosomes toward the cytoplasm, to be available for
proteasomal degradation into peptides for loading onto
MHC I molecules. The mechanisms governing such intracellular antigen sorting are unclear.
It has recently been demonstrated that internalized
proteins are not generally entered into a common pool
of early endosomes [9], but rather into distinct populations of early endosomes with different maturation
kinetics: one matured rapidly into late endosomes
and one of them was more stable. Sorting of cargo into
these subsets occurred already at the plasma membrane, and was likely because of the association of
the endocytic receptor with adaptor proteins. Thus,
antigen sorting may be primarily determined by the
endocytosis mechanism, which of course does not
exclude an additional role of subsequent intracellular
sorting from endosomes.
Such endocytosis-dependent routing into different
endosomal compartments has recently been shown to
Current Opinion in Immunology 2008, 20:89–95
be crucially important for antigen presentation [10].
Soluble antigen taken up by the mannose receptor
(MR) was routed toward a mildly acidic stable early
endosomal compartment for exclusive presentation on
MHC I molecules. By contrast, pinocytosed and scavenger receptor (SR)-endocytosed antigens were targeted rapidly toward lysosomes, where they were
processed only for MHC-II-restricted presentation.
These results demonstrated that antigens intended
for crosspresentation do not have to be diverted intracellularly from those for MHC II presentation, as they
were separated already during endocytosis. Hence, in
contrast to the time-dependency of presentation
of particulate antigens, presentation of soluble antigens appears to depend on intracellular localization
(Figure 1).
Endocytic properties of the MR and
consequences for antigen presentation
The MR is well established to target antigen to early
endosomes, but not to lysosomes [10,11–13]. Ligand
binding to the MR even prevented fusion of phagosomes
with lysosomes [14]. However, this inability for lysosomal
antigen targeting seemed to be at conflict with reports
describing lysosomal targeting [15] and MHC-IIrestricted presentation of mannosylated antigens
[16,17]. These early studies had used mannan, a mannose
polymer, as inhibitor of MR-mediated uptake, because
MR-deficient mice had not yet been available. More
recent studies revealed that highly mannosylated
antigens were not taken up by the MR, but instead by
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Endocytosis and antigen-presentation Burgdorf and Kurts 91
to activate CD8+ T cells [10,28]. DEC-205 facilitated
both CD4+ and CD8+ T cell activation [12,28]. Further
examples of receptors that could target both MHC-Iloading and MHC-II-loading include the B cell receptor
(BCR) and certain Fc receptors [30,31]. Langerin is a
further receptor linked to CD8+ T cell activation [32], and
its cargo is also excluded from lysosomes [33]. Endo180
and SIGNR1, whose role in antigen presentation is
unknown, are examples of further receptors with early
endosomal routing [33,34]. Table 1 summarizes the properties of the receptors discussed in this review. It is
possible that these associations are further affected by
intrinsic properties of the expressing cell, the nature of
the antigenic cargo, or by species-specific receptor variations.
DC-SIGN [18], which is also inhibited by mannan.
However, DC-SIGN targets antigen toward MHC-IIrestricted presentation [19]. Thus, it appears possible
that some functions formerly attributed to the MR may
have been DC-SIGN-mediated.
A widely used approach for targeting antigen to cell
surface receptors is the use of specific antibodies coupled
to model antigens. Some studies using this technique
reported MHC-II-restricted presentation of MR-targeted
model antigens [20–22]. However, antibody-mediated
crosslinking of the MR has been shown to functionally
mature DC and to change their cytokine secretion profile
[23]. Furthermore, crosslinking of dectin-1, a different
lectin receptor with endocytic activity, by the b-glucan
polymer, zymosan, resulted in routing into lysosomes, as
opposed to monovalent b-glucans, which were targeted to
nonlysosomal endosomes [24]. These findings demonstrated that receptor crosslinking can profoundly alter its
intracellular routing, providing an alternative explanation
for the observed MHC-II-restricted presentation resulting from antibody-mediated MR targeting. Moreover,
there is also a circulating soluble form of the MR, which
may exert distinct effects on antigen presentation in vivo
[25].
Expression of endocytic receptors on
distinct APC subsets
The various APC subtypes are specialized at distinct
types of antigen presentation, and especially crosspresentation is tightly restricted [35]. Conventional CD8+
DCs are generally regarded the most proficient crosspresenting APCs, and this has been ascribed to their
unique antigen-processing capabilities [28]. However,
CD8 per se does not seem to be functionally involved in
crosspresentation, because also CD8 DCs [36–39],
certain macrophages [10,40], B cells [30], and liversinusoidal endothelial cells [41] could do so under certain circumstances. The regulated expression of endocytic receptors linked to crosspresentation offers a
mechanistic explanation for these ostensibly conflicting
findings. It would also be consistent with the recent
demonstration that capturing large antigen amounts is
insufficient for crosspresentation [42]. Future studies
have to determine the relative importance of selective
receptor expression [10] and processing capabilities
[28] in MHC-I-restricted and MHC-II-restricted antigen presentation.
Further endocytosis receptors linked to
distinct target organelles and selective
antigen presentation
An association with selective MHC-I-restricted or MHCII-restricted antigen presentation has been described for
several receptors. For example, DC-SIGN-targeted antigen toward lysosomes and facilitated activation of CD4+
T cells [19,26]. Other receptors known to mediate MHCII-restricted presentation include murine SRs, DEC-205,
DCIR2, dectin-1, and MGL [10,12,27,28,29]. For SRs,
DEC-205, and MGL, lysosomal targeting has been
demonstrated [10,12,29]. SRs and DCIR2 were unable
Table 1
Examples of endocytosis-dependent antigen routing and presentation
Receptor
Cargo
Organelle targeted
MR (CD206)
Ovalbumin
a-MR mAb
Early endosomes
?
+
?
Langerin (CD207)
DEC-205 (CD205)
SR
DC-SIGN (CD209a)
DCIR2
Dectin-1
MGL
Fc receptors
Virus-like particles, a-langerin mAb
a-DEC-205 mAb
Ovalbumin
a-DC-SIGN mAb
a-DCIR2 mAb
a-Dectin-1 mAb
a-MGL mAb
a-Fc receptor mAb
Early endosomes
Lysosomes
Lysosomes
Lysosomes
?
?
Lysosomes
?
+
+
?
?
+
?
+
+
+
+
+
+
+
B cell receptor
Trinitrophenol group
Hen egg lysozyme
?
?
+
?
?
+
www.sciencedirect.com
Crosspresentation
?
MHC-II-restricted
presentation
+
Current Opinion in Immunology 2008, 20:89–95
92 Antigen Processing and Recognition
Table 2
Murine antigen-presenting cells and expression of endocytosis receptors
APC subset
Endocytosis receptors
Conventional CD8 DC
Conventional CD8+ DC
Langerhans cell
B cells
Bone-marrow-derived DC
Bone-marrow-derived macrophages
DCIR2, DC-SIGN (CIGR), dectin-1
DEC-205, MR
Langerin, DEC-205
B cell receptor
MR
MR, SR
By regulating receptor expression, APC may control their
ability to crosspresent, even at the level of selected
antigen classes. This may explain why certain lectin
receptors, such as the MR [10], DEC-205 [28], or
langerin [43], are selectively expressed by crosspresenting
APCs. These receptors may be more useful to identify
crosspresenting APCs than the surrogate marker CD8.
Conversely, the endocytotic receptors dectin-1 [27],
DCIR [28], SR [10], and DC-SIGN, whose murine
equivalent is also known as CIRE [26], are primarily
expressed on CD8 DCs that cannot crosspresent
(Table 2), consistent with selective antigen introduction
into the MHC-II-loading compartment(s).
DEC-205 is distinguished by its ability to introduce
antigen into both the MHC-I-loading and MHC-II-loading compartments. This capability may be important for
crosspriming, that is, the immunogenic activation of
CD8+ T cells by crosspresentation, because specific
CD4+ T cell help is required to ‘license’ DCs for crosspriming [44]. Thus, the same DC must present antigen to
specific CD4+ and CD8+ T cells, and consequently it
must capture and introduce antigen into both the MHC-Iloading and MHC-II-loading compartments. In addition
to DEC-205, this is the case also for Fc receptors, and may
support their ability to recognize antibody-opsonized
antigen for efficient T cell priming. For antigens that
do not bind to receptors targeting both compartments,
either binding to two receptors with overlapping specificity and distinct routing properties would be required.
Alternatively, crosspresenting DC may use pinocytosis to
obtain antigen for MHC-II-restricted presentation [10].
This avoids situation in which a crosspresenting DC that
has captured antigen for CD8+ T cell activation, lacks a
suitable receptor for cognate presentation to licensing
CD4+ T cells.
Loading of antigenic peptide on MHC I
molecules
Stable early endosomes have recently been described as
compartments that simultaneously contained antigens
intended for crosspresentation and crosspresented antigen,
that is, antigen-derived peptides loaded onto MHC I
molecules [10]. This colocalization shed new light on
the longstanding question regarding the identity of the
elusive organelle of crosspresentation. At least three
Current Opinion in Immunology 2008, 20:89–95
Ability to crosspresent
No
Yes
Yes
Yes
Yes
Yes
mechanistic explanations can theoretically account for this
observation (Figure 2). First, antigens could be degraded
by endosomal proteases, for example, cathepsins and
subsequently be loaded onto MHC I molecules within
endosomes (Figure 2a), which has been referred to as TAPindependent crosspresentation [45,46]. However, most
studies examining the cell biology of crosspresentation
reported a requirement of TAP and the proteasome [3–
6,10,47,48,49]. Nevertheless, TAP-independent crosspresentation may play a role for some antigens or antigenic
epitopes. A second possibility involves antigen transport
into the cytoplasm, degradation by the cytoplasmic proteasome, and reimport of antigen-derived peptides by TAP
into the ER (Figure 2b), which contains the machinery for
MHC I loading [50]. From the ER, MHC I/peptide complexes could be transported either toward the early endosomal compartment (where they colocalized with antigen
as observed [10]) and from there toward the cell membrane. Alternatively, they could be transported from the
ER directly to the cell membrane, in which case subsequent internalization of these complexes would have
to be proposed to explain their detection in early endosomes [10]. Third, antigen-derived peptides might be
reimported from the cytoplasm into early endosomes, and
MHC I loading might occur there (Figure 2c). This of
course would require the presence of the MHC-I-loading
machinery in these endosomes, which is supported by the
detection of calnexin in OVA-containing ‘ER-like structures’, which were of endosomal morphology and spatially
separated from the perinuclear ER [6]. This latter mechanism is reminiscent of that proposed for crosspresentation
of particulate antigens [4–6], which involved antigen
export from phagosomes, cytoplasmic processing by the
proteasome, and reimport of peptides into phagosomes by
TAP in the phagosomal membrane. Further support for the
third mechanism came from a study showing that
deficiency of ERAP1, which is involved in endogenous
peptide loading in the ER, did not affect crosspresentation
of soluble antigen, suggesting that this process may not
take place in the ER [49]. The recent identification of
endocytosis mechanisms and organelles dedicated to crosspresentation may permit clarifying which of these three
mechanisms is relevant.
Finally, it needs to be mentioned that additional mechanisms for crosspresentation have been described. Thus,
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Endocytosis and antigen-presentation Burgdorf and Kurts 93
Figure 2
Putative intracellular mechanisms of crosspresentation. (a) Antigens are degraded by endosomal proteases and loaded within endosomes on
MHC I molecules. (b) Antigens are exported from endosomes into the cytoplasm and degraded by the proteasome. Antigen-derived peptides are
transported by TAP into the ER, where they are loaded onto MHC I molecules. These complexes can then be transported either toward early
endosomes and onto the cell membrane, or directly from the ER toward the cell membrane. From there they might reach early endosomes by
recycling. (c) Antigens are degraded by the cytosolic proteasome, and resulting peptides are transported by TAP into the endosomes for MHC I
loading.
antigen-derived peptides from donor cells can directly
enter the cytosol of DC by intercellular exchange through
GAP junctions [51]. Furthermore, exogenously added
b2-microglobulin, a component of the MHC I complex,
has been shown to directly enter the ER by unknown
routes [52]. Such routing may allow crosspresentation by
utilizing the processing mechanisms for endogenous antigens. It remains to be clarified whether ER access is
generally possible, or only applies to a subset of antigens.
Conclusions
The endocytosis mechanisms can predetermine intracellular antigen routing, processing, and presentation to
CD4+ and/or CD8+ T cells. Pinocytosis and certain
receptors, for example, DC-SIGN, DCIR2, or SRs, target
antigen toward acidic late endosomes/lysosomes, and thus
www.sciencedirect.com
for MHC-II-restricted antigen presentation. By contrast,
the MR, and perhaps also other receptors, can convey
antigen into distinct early endosomes that neither
mature, acidify, nor fuse with lysosomes, but instead
remain stable over extended periods within APCs. Such
antigen is exclusively used for crosspresentation. Thus,
only MHC-II-restricted antigen presentation requires
antigen transport into lysosomes. This model of antigen
presentation is consistent with the selective expression
of distinct lectin endocytosis receptors on crosspresenting or non-crosspresenting DCs, and may apply also to
other APC classes. By contrast, cell-associated antigen is
routed into phagosomes, which facilitate both MHC-Irestricted and MHC-II-restricted presentation, albeit at
different maturation stages. Crosspresentation of soluble
and cell-associated antigen is governed by distinct
Current Opinion in Immunology 2008, 20:89–95
94 Antigen Processing and Recognition
mechanisms [48,49,52,53]. However, for both soluble
and cell-associated antigen, the cell-biological mechanisms of crosspresentation remain unclear. In particular,
the elusive crosspresentation organelle remains to be
identified. Answering this question not only would
advance knowledge on the basic mechanisms of antigen
presentation but may also contribute to the design of
more effective vaccines.
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