Citation
Jordens, I. (2005, November 23). Transport of Lysosome-Related Organelles. Retrieved
from https://hdl.handle.net/1887/4341
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Corrected Publisher’s Version
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Licence agreement concerning inclusion of doctoral thesis in the
Institutional Repository of the University of Leiden
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Scope of the Thesis
The endocyt
i
c pat
hway i
s essent
i
al
for t
he defence agai
nst
pat
hogens. Vari
ous pat
hogens
are i
nt
ernal
i
zed some of i
t
s prot
ei
ns (ant
i
gens) are subsequent
l
y degraded whi
l
e t
ransport
ed
t
hrough t
he endocyt
i
c pat
hway. In t
hi
s way,
smal
l
i
mmuno genet
i
c pept
i
des are generat
ed
whi
ch are ul
t
i
mat
el
y l
oaded ont
o M HC cl
ass II mol
ecul
es i
n t
he speci
al
i
zed M HC cl
ass
II-cont
ai
ni
ng compart
ment
s (M IIC). At
t
he same
t
i
me M HC cl
ass II mol
ecul
es are synt
hesi
zed
i
n
t
he
ER
and
t
arget
ed
vi
a
t
he
Gol
gi
Apparat
us
t
o
t
he
M IIC.
Thi
s
l
ysosomal
-rel
at
ed
organel
l
e
forms t
he i
deal
envi
ronment
for l
oadi
ng of t
he ant
i
geni
c pept
i
des ont
o M HC cl
ass II
mol
ecul
es. Aft
er l
oadi
ng,
M HC cl
ass II mol
ecul
es are t
ransport
ed t
o t
he pl
asma membrane
where
t
he
pept
i
de-M HC
cl
ass
II
compl
ex
i
s
present
ed
t
o
CD4+
T
cel
l
s.
The
fi
rst
part
of
t
he
introduction
gi
ves
a
general
overvi
ew
of
t
he
process
of
M HC
cl
ass
II
l
oadi
ng wi
t
h pept
i
des. The i
nvol
vement
of HLA-DM and -DO are di
scussed as wel
l
as t
he
possi
bl
e use of M HC cl
ass II-pept
i
des i
n i
mmunot
herapy for cancer. The second part
of t
he
introduction
deal
s wi
t
h t
he current
fi
ndi
ng t
hat
Rab prot
ei
ns are not
onl
y found associ
at
ed
wi
t
h t
he fusi
on machi
nery of i
nt
racel
l
ul
ar vesi
cl
es,
but
are oft
en l
i
nked t
o mot
or prot
ei
ns as
wel
l
.
InChapter 2
we
l
ook
i
n
cl
oser
det
ai
l
t
o
t
he
t
ransport
of
t
he
M IIC.
By
l
abel
i
ng
t
he
E-chai
n
of
t
he
cl
ass
II
DR1
wi
t
h
GFP,
we
were
abl
e
t
o
fol
l
ow
t
he
M IIC
i
n
l
i
vi
ng
cel
l
s.
St
ri
ki
ng
i
s
t
he
bi
-di
rect
i
onal
t
ransport
of
t
hese
compart
ment
s.
W e
det
ermi
ned
t
hat
t
hi
s
bi
-di
rect
i
onal
i
t
y
was
faci
l
i
t
at
ed by t
he al
t
ernat
i
ng act
i
ons of t
wo mi
crot
ubul
e-based mot
ors,
ki
nesi
n and dynei
n.
The regul
at
i
on of t
hi
s t
ransport
occurs vi
a t
he smal
l
GTPase Rab7 and i
t
s effect
or RILP,
whi
ch i
s descri
bed i
n Chapter 3. RILP,
upon bi
ndi
ng t
o act
i
ve Rab7,
i
s abl
e t
o recrui
t
t
he
mi
nus-end mot
or compl
ex dynei
n-dynact
i
n ont
o l
ysosomal
compart
ment
s.
Thereby
t
ransport
t
owards t
he mi
crot
ubul
e-organi
zi
ng cent
er (M TOC) i
s st
i
mul
at
ed. As a resul
t
,
l
ysosomal
compart
ment
s
form
a
dense
cl
ust
er
around
t
he
M TOC.
Recent
l
y
we
found
a
nat
ural
occurri
ng
spl
i
ce
vari
ant
of
RILP,
l
acki
ng
exon
VII,
whi
ch
i
s
unabl
e
t
o
recrui
t
t
he
dynei
n-dynact
i
n
mot
or
compl
ex. The charact
eri
st
i
cs of t
hi
s vari
ant
and i
t
s i
mpl
i
cat
i
on for t
he current
underst
andi
ng
of
RILP
funct
i
oni
ng
are
out
l
i
ned
i
n
Chapter 4
.
M IIC
are
not
t
he
onl
y
l
ysosomal
compart
ment
s
movi
ng
i
n
a
bi
-di
rect
i
onal
fashi
on
t
hrough
t
he cel
l
. Convent
i
onal
l
ysosomes and l
at
e endosomes,
and phagosomes al
so move bi
-di
rect
i
onal
vi
a
t
he
act
i
on
of
ki
nesi
n
and
dynei
n
al
ong
t
he
mi
crot
ubul
es.
Chapter 5
descri
bes
how st
i
mul
at
i
on of mi
nus-end t
ransport
by expressi
on of RILP,
can l
ead t
o t
he ki
l
l
i
ng of
Salmonella bact
eri
a. Normal
l
y Salmonella survi
ves i
n a so-cal
l
ed Salmonella-cont
ai
ni
ng
vacuol
e (SCV) by act
i
vel
y prevent
i
ng fusi
on wi
t
h mat
ure,
degradat
i
ve l
ysosomes. W e now
show
t
hat
upon
expressi
on
of
RILP,
dynei
n
i
s
massi
vel
y
recrui
t
ed
ont
o
t
he
SCV
whi
ch
l
argel
y
st
i
mul
at
es fusi
on wi
t
h mat
ure l
ysosomes. As a resul
t
,
i
nt
racel
l
ul
ar Salmonella survi
val
decreases
dramat
i
cal
l
y.
In mel
anocyt
es,
a speci
al
i
zed l
ysosomal
compart
ment
exi
st
s besi
des t
he convent
i
onal
l
ysosomes,
t
he mel
anosome. M el
anosomes are t
he fact
ori
es i
n whi
ch mel
ani
n i
s synt
hesi
zed
and st
ored. Upon st
i
mul
at
i
on wi
t
h hormones or UV l
i
ght
,
mel
anocyt
es secret
e t
hei
r
mel
anosomes,
whi
ch
are
t
aken
up
by
t
he
nei
ghbori
ng
kerat
i
nocyt
es
and
provi
de
col
or
i
n
hai
r
and
ski
n.
Chapter 6
deal
s
wi
t
h
t
wo
GTPases
and
t
wo
mot
or
prot
ei
ns
act
i
ve
i
n
t
he
t
ransport
of
mel
anosomes. W hereas Rab7 act
s i
n a more earl
y st
age,
regul
at
i
ng t
he mi
crot
ubul
e-based
dynei
n t
ransport
vi
a RILP,
Rab27a act
s at
l
at
er st
ages capt
uri
ng t
he mel
anosomes i
n t
he
peri
pheral
act
i
n
vi
a
t
he
act
i
n-based
M yosi
n
Va
mot
or.
molecules and their role in oncogenesis
Adapted from:
Adv Cancer Res. 93:129-158 (2005)
Introduction
A brief introduction in the process of antigen presentation
MHC class II molecules present fragments from proteins degraded in the endocytic
pathway (Cresswell, 2000;
Wubbolts and Neefj
es, 1999) (figure 1). MHC class II molecules
are composed of an D and E chain that assemble in the ER into an DE heterodimer.
Subsequently, a third chain, the invariant chain or Ii, interacts with this heterodimer to form a
heterotrimer. In fact, a trimer of this heterotrimer is formed resulting in a nonameric complex
(Cresswell, 1994;
Marks et al., 1990;
Roche et al., 1991). Ii acts as a sort of a pseudosubstrate
by allowing a small segment (called CLIP for Class II-associated Ii peptide) to enter the
peptide-binding groove of MHC class II. Moreover, Ii is necessary for transport out of the ER
as illustrated in mice lacking Ii which show a reduced surface expression of MHC class II
(Bikoff et al., 1993;
Viville et al., 1993).
Whereas most proteins are transported via the Golgi directly to the plasma membrane, Ii
targets MHC class II molecules from the trans-Golgi network to late endosomal structures,
collectively called MIIC for MHC class II-containing compartments (Neefj
es et al., 1990). In
the MIIC all the requirements for efficient peptide loading of MHC class II are concentrated.
First, proteases that degrade Ii until only the CLIP fragment is left in the peptide binding
groove of MHC class II molecules (Neefj
es and Ploegh, 1992). Second, proteases, reductases
and unfoldases that process antigenic fragments that have entered the cell by
receptor-mediated or fluid-phase endocytosis (Lennon-Dumenil et al., 2002). Finally, HLA-DM which
mediates the exchange of the CLIP fragment for fragments generated from the endocytosed
antigens (Sanderson et al., 1994). The activity of HLA-DM in turn can be controlled by a
chaperone-of-chaperones called HLA-DO (Denzin et al., 1997;
Lilj
edahl et al., 1996;
van
Ham et al., 1997). Thus, in these specialised MIIC the unique combination of dedicated
(endosomal) chaperones and proteolytic activity supports proper antigen loading of MHC
class II molecules. Loaded MHC class II molecules are subsequently transported to the
plasma membrane for presentation of endocytosed antigens to CD4
+T cells (Germain and
Rinker, 1993;
Neefj
es and Ploegh, 1992).
Fig. 1 Peptide loading of M HC class II and M HC class I molecules.
The invariant chain, a transporting pseudopeptide
As discussed above, MHC class II molecules can encounter at least three different
specialised chaperones during its existence. The formation of the MHC class II DE
heterodimer is the first step in the formation of the MHC class II complex in the ER and is
assisted by various common chaperones like BiP and PDI (Bonnerot et al., 1994; Cotner and
Pious, 1995; Nijenhuis and Neefjes, 1994; Schaiff et al., 1992). Rapidly after this assembly
step, the first dedicated chaperone Ii is co-assembled (Cresswell, 1994; Marks et al., 1990;
Roche et al., 1991). Ii is usually expressed in molar excess over MHC class II DE
heterodimers and is retained in the ER. Whereas Ii supports exit of MHC class II DE
heterodimers from the ER, the reverse is also the case. MHC class II DE heterodimers are
required for release of Ii from the ER (Bikoff et al., 1993; Marks et al., 1990; Viville et al.,
1993).
Ii is a type II transmembrane glycoprotein containing a short amino-terminal cytoplasmic
domain, a single transmembrane domain, a domain that occupies the peptide-binding groove
of MHC class II (called Class-II-associated Ii peptide or CLIP), and a carboxyl-terminal
trimerisation motif (figure 2). Ii forms trimers that interact with dimers of MHC class IIDE in
the ER (Cresswell, 1994; Marks et al., 1990; Roche et al., 1991) (figure 1). The interaction of
Ii with MHC class II is necessary for proper folding and supports transport of MHC class II
molecules (Anderson and Miller, 1992; Cresswell, 1996; Marks et al., 1995a; Viville et al.,
1993) from the ER to endosomal structures (Bikoff et al., 1993).
Ii, however, not only functions as a mediator in transport. Early in assembly, the CLIP
segment of Ii enters the MHC class II peptide-binding groove. This acts as a pseudopeptide
preventing premature loading of MHC class II with peptides that have entered the ER for
binding to MHC class I molecules (Busch et al., 1996). In addition, peptide (or
pseudopeptide) binding is required to pass the ‘ER quality control system’ for transport to the
endocytic pathway (Bikoff et al., 1993; Viville et al., 1993). After ER exit the vast majority of
MHC class II/
Ii complexes enters the endocytic pathway (Neefjes et al., 1990), although a
small percentage is transported directly to the plasma membrane via the secretory pathway
(Lamb et al., 1991) followed by rapid internalisation and sorting into the endocytic pathway
(Brachet et al., 1999; Roche et al., 1993).
Fig. 2 Structural overview of the p31 isoform of the human invariant chain.
The cytoplasmic domain of Ii contains two di-leucine motifs (figure 2), which are
necessary for sorting of MHC class II molecules to the MIIC and also for internalisation from
the plasma membrane (Bakke and Dobberstein, 1990; Lotteau et al., 1990; Nijenhuis et al.,
1994; Odorizzi et al., 1994; Pieters et al., 1993; Pond et al., 1995). There is some debate about
how the MHC class II complexes traffic to the MIIC. Some reports describe trafficking via
early endosomes to MIIC (Brachet et al., 1999; Pond and Watts, 1999), but most show direct
targeting from the trans-Golgi network to the MIIC (Benaroch et al., 1995; Davidson, 1999;
Neefjes et al., 1990; Peters et al., 1991). In all cases the MHC class II complexes are targeted
to the pre-lysosomal MIIC compartment.
Processing of the invariant chain
Once inside the endocytic pathway, Ii is degraded by various proteases in a processive
manner. Ii degradation is essential for transport of antigen loaded MHC class II molecules
from the MIIC to the plasma membrane. Although cathepsin B and D were originally claimed
to be responsible for degradation of Ii, this concept was left when it was observed that Ii
degradation proceeded normally in mice lacking these proteases (Deussing et al., 1998;
Villadangos et al., 1997). Instead, Ii degradation involves more specific proteases like
cathepsin S and L. Inhibition of cathepsin S impaired MHC class II antigen presentation and
Ii degradation (Riese et al., 1998; Riese et al., 1996). A marked tissue specific expression
profile is observed for the cathepsins. In macrophages cathepsin S is up- and cathepsin L is
down-regulated upon interferon Jstimulation (Beers et al., 2003). Whereas peripheral antigen
presenting cells contain relatively high cathepsin S levels (Beers et al., 2003; Honey et al.,
2001), cathepsin L appears to be crucial for Ii degradation in cortical tissue endothelial cells
(Honey et al., 2002; Nakagawa and Rudensky, 1999). Thus, cathepsin S and L are both
important with partially overlapping activities for Ii degradation, although other (currently
unknown) proteases will be involved in other steps of this degradation.
In conclusion, several proteases are required for one simple but crucial act, the removal
of a transporting chaperone 1-3 hours after assembly of the MHC class II/Ii nonamer. This is
critical for the exchange of remaining CLIP fragments for antigenic peptides and for the
transport of MHC class II to the plasma membrane.
The invariant chain, more than just a M HC cl
ass II chaperone
Invariant chain does not merely function as a MHC class II chaperone preventing peptide
loading in the ER, stimulating exit from the ER and modulating antigenic peptide loading, but
it may have additional functions as well. The development from immature to mature B-cells is
impaired in Ii-deficient mice. These B-cells arrest in an immature stage (Kenty and Bikoff,
1999; Shachar and Flavell, 1996). The N-terminal cytoplasmic domain of Ii is required for
B-cell maturation, since expression of only this domain suffices to stimulate B-B-cell maturation
(Matza et al., 2002b). The Ii cytosolic domain diffuses from MIIC into the nucleus where it is
supposed to activate NF-NB signalling which then results in B-cell maturation (Matza et al.,
2002a).
HLA-DM , editor for antigenic peptide l
oading of M HC cl
ass II mol
ecul
es
identified as HLA-DMA and HLA-DMB which assemble into HLA-DM (H2-M in mice), a
non-polymorphic type I membrane protein with high similarity in sequence and structure to
MHC class II molecules (Cho et al., 1991; Fling et al., 1994; Kelly et al., 1991; Mellins et al.,
1991; Morris et al., 1994). After assembly in the ER, HLA-DM is transported to MIIC
through a tyrosine-based targeting signal in the cytoplasmic tail of HLA-DMB (Copier et al.,
1996; Marks et al., 1995b). Although HLA-DM accumulates in MIIC, it probably recycles via
the plasma membrane by efficient re-internalisation mediated by the tyrosine-motif in the
HLA-DMB tail (Arndt et al., 2000; van Lith et al., 2001).
HLA-DM deficient cells and mice express surface MHC class II molecules loaded with
the Ii-degradation fragment CLIP instead of antigenic peptides (Ceman et al., 1994; Fling et
al., 1994; Fung-Leung et al., 1996; Martin et al., 1996; Miyazaki et al., 1996; Morris et al.,
1994; Riberdy et al., 1992). Thus, although some spontaneous exchange of CLIP for antigenic
fragments can occur in the acidic MIIC (Avva and Cresswell, 1994), efficient exchange
requires HLA-DM to release CLIP and low affinity peptides, while allowing high affinity
peptides to remain associated (Denzin and Cresswell, 1995; Kropshofer et al., 1996; Lovitch
et al., 2003; Sherman et al., 1995; Sloan et al., 1995; van Ham et al., 1996; Weber et al.,
1996). Further in vitro experiments showed that the interaction between HLA-DM and MHC
class II molecules and the ‘activity’ of HLA-DM were facilitated by acidic pH, as found in the
MIIC (Kropshofer et al., 1997; Sanderson et al., 1996; Ullrich et al., 1997; vogt et al., 1997).
HLA-DM appears to stabilize MHC class II molecules devoid of peptide to allow binding of
high affinity peptides and at the same time, as a true chaperone, prevents the aggregation of
‘empty’ MHC class II molecules (Denzin et al., 1996; Kropshofer et al., 1997).
The structure of HLA-DM reveals a molecule with a high structural identity to MHC
class II molecules (figure 3). One major difference is the absence of a MHC class II
peptide-binding groove in HLA-DM, which renders it unable to bind peptides (and the invariant
chain) (Fremont et al., 1998; Mosyak et al., 1998). A co-crystal of HLA-DM and MHC class
II molecules has not been generated, but mutational studies have revealed areas in the top part
(peptide-binding groove) of MHC class II and HLA-DM as interacting segments (Pashine et
al., 2003; Stratikos et al., 2002). MHC class II molecules are highly polymorphic and
different MHC class II alleles present different fragments from the same antigen. Still, Ii as
well as HLA-DM are non-polymorphic and interact with all polymorphic MHC class II alleles
(Robinson et al., 2001). As a consequence, the binding affinity of CLIP for MHC class II
Fig. 3 The structure of HLA-DM shows high structural identity to MHC class II molecules.
molecules differs for the different MHC class II haplotypes, possibly resulting in a different
dependency on HLA-DM (Doebele et al., 2003). Whether this results in differences in peptide
loading of MHC class II remains unclear.
HLA-DO, the chaperone of chaperones
As described, efficient loading of MHC class II with specific antigenic peptides is tightly
regulated by the chaperones Ii and HLA-DM. More recently the attention shifted to another
MHC class II look-a-like, also encoded in the MHC locus. Two genes encoding for
HLA-DOA and HLA-DOB were identified that assemble into a HLA-DO (or H2-O the murine
homologue of HLA-DO) heterodimer (Tonnelle et al., 1985; Young and Trowsdale, 1990).
Like HLA-DM, HLA-DO has a very high sequence identity to HLA-DR molecules, which
suggests that they arose from recent gene duplication (van Lith et al., 2002). HLA-DO is also
a non-polymorphic heterodimer with lysosomal targeting sequences located in the
cytoplasmic tail of HLA-DOB (van Lith et al., 2001). Unlike HLA-DMB, HLA-DOB
contains two putative targeting signals, a di-leucine motif and a tyrosine-based motif (van
Lith et al., 2001).
Whereas DM is always co-expressed with MHC class II molecules in APCs,
HLA-DO is only expressed on a subset of thymic medullary epithelium and in immature B cells
(Douek and Altmann, 1997; Karlsson et al., 1991; Tonnelle et al., 1985). Moreover, both
HLA-DO and HLA-DM are rapidly down-regulated upon activation of B cells (Roucard et al.,
2001). A stable interaction is formed between HLA-DO and HLA-DM, and targets HLA-DO
to the MIIC (Liljedahl et al., 1996). Upon deletion of its targeting signals, HLA-DO is still
targeted to the MIIC via HLA-DM (van Lith et al., 2001). Subsequently, the HLA-DM/DO
heterotetramer recycles between MIIC and the plasma membrane although it accumulates in
MIIC (van Lith et al., 2001).
HLA-DO acts as a negative regulator of HLA-DM since MHC class II molecules loaded
with the CLIP fragment appeared at the plasma membrane in response to ectopic expression
of HLA-DO or overexpression of H2-O in transgenic mice (Brocke et al., 2003; Denzin et al.,
1997; van Ham et al., 2000; van Ham et al., 1997). Mice deficient for H2-O have only mild
phenotypes, including an increase in antibody titer in plasma suggesting that B cell
proliferation is less tightly controlled (Liljedahl et al., 1998; Perraudeau et al., 2000). Further
studies revealed that HLA-DO altered the pH sensitivity of HLA-DM in supporting peptide
loading of MHC class II molecules in vitro. Apparently, HLA-DO acts as a pH sensor
restricting HLA-DM activity to more acidic (late endosomal) structures (van Ham et al.,
2000). The function of HLA-DO is not fully understood, the assumption is that the activity of
B cells should be tightly controlled, implying that antigenic peptide loading of MHC class II
should primarily occur with antigens recognized by surface immunoglobulins. The activity of
HLA-DO skews peptide loading to the late endosomal structures where B cell
receptor-mediated antigens are processed. HLA-DO may thus play a critical role in controlling B cell
activation by regulating the activity of HLA-DM.
From the MIIC to the plasma membrane
organising center (MTOC) toward the plasma membrane (Wubbolts et al., 1996). This
transport is similar to late endosomal and lysosomal transport and occurs in a bi-directional
manner and in a stop-and-go fashion along the microtubules, mediated by the alternate
activities of the dynein/dynactin and kinesin motor proteins (Wubbolts et al., 1999). What
controls these motor protein activities is largely unclear but dynein/dynactin-mediated
transport toward the minus-end involves at least the activity of the small GTPase Rab7 and its
effector protein RILP (Jordens et al., 2001).
Finally, the MIIC reaches the end of the microtubule at the cortical actin cytoskeleton just
underneath the plasma membrane. How this last step occurs is unclear, but ultimately the
MIIC fuses with the plasma membrane, as shown by electron microscopy (Raposo et al.,
1996; Wubbolts et al., 1996). At the plasma membrane, part of the intracellular content (the
internal vesicles in a multivesicular body) is secreted in the form of so-called exosomes
(Raposo et al., 1996; Zitvogel et al., 1998). The majority of the internal structures of the MIIC
probably fuse back to the plasma membrane followed by rapid internalisation of the late
endocytic MIIC proteins via their internalisation signals (Arndt et al., 2000; van Lith et al.,
2001). Subsequently, these proteins are transported back to the MIIC through the endocytic
pathway. Since only part of the MHC class II molecules can be internalised, MHC class II
accumulates at the plasma membrane (Pinet et al., 1995; Reid and Watts, 1990).
After internalisation, a fraction of the MHC class II molecules is recycled back to the
plasma membrane. In monocytes, the reappearance of MHC class II at the plasma membrane
is controlled by interleukin 10 (Koppelman et al., 1997). Treatment with IL-10 results in a
strong reduction of surface MHC class II molecules possibly by affecting the Rab7 pathway,
which in turn controls dynein motor-mediated MIIC transport (our unpublished results). This
is the first example of regulation of MHC class II responses by manipulation of the last step in
intracellular transport of MHC class II molecules to the cell surface.
An alternative route of MHC class II molecules from the MIIC to the plasma membrane
has been proposed for dendritic cells (Boes et al., 2002; Chow et al., 2002; Kleijmeer et al.,
2001). Upon activation of DCs, the MIIC appears to alter its morphology resulting in the
formation of long tubular structures extending into the periphery. Live imaging of these cells
revealed that these class II-positive structures, similar to the conventional MIIC, move in a
microtubule-dependent manner (Boes et al., 2002). Probably in response to the gross
alteration of the cytoskeleton of activated dendritic cells, the MHC class II molecules move
more in the direction of the contact site with a specific T cell. Surprisingly, no accumulation
of GFP-tagged MHC class II molecules was observed in the ‘immunological synapse’
between the DC and the T cell (Boes et al., 2002). The exact function of this directed
transport of MIIC-derived tubules after DC activation still has to be revealed.
Thus two modes of transport of MHC class II molecules from MIIC to the plasma
membrane have been reported; direct transport and fusion of MIIC with the plasma membrane
and the formation of tubular structures. In either case, transport requires motor-based
microtubule transport likely to be mediated by dynein/dynactin and kinesin motor proteins,
with the small GTPase Rab7 as one of the controllers of this transport step.
Interfering with antigen presentation by MHC class II molecules
Promoting antigen presentation
proteases at different stages of biosynthesis. Obviously, affecting one or more of these
enzymes can positively or negatively influence antigen presentation. For instance, MHC class
II antigen presentation can be improved when antigens are more efficiently acquired and
targeted to MIIC. Macrophages and monocytes, in contrast to B cells, are able to internalise
large volumes. This implies that many antigenic fragments have to compete for access to
MHC class II molecules in the MIIC. More selective uptake of antigen using surface
immunoglobulins in B cells (Lanzavecchia, 1985; Rock et al., 1984; Siemasko and Clark,
2001), Fc-receptors on macrophages and DCs (Fanger et al., 1997; Guyre et al., 1997) or
mannose-receptors on DCs (Engering et al., 1997) will strongly improve antigen presentation
by MHC class II molecules (Lanzavecchia, 1996). Cells may also alter the conditions for
antigen presentation in MIIC. Best studied are DCs that acidify the MIIC upon activation
(Trombetta et al., 2003), and B cells that down-regulate HLA-DO upon activation (Roucard et
al., 2001). In both cases, antigen presentation by MHC class II molecules is more efficient.
Inhibiting antigen presentation
If activation of MHC class II antigen presentation is an option, the reverse is almost
certainly true as well. For instance, Th2 cell activity controlling immune responses can inhibit
class II antigen presentation. Another manner to inhibit MHC class II responses is by
interfering with endosomal proteases, as was first shown by using leupeptin. Leupeptin is a
protease inhibitor that inhibits complete degradation of Ii (Cresswell et al., 1990; Neefjes and
Ploegh, 1992). Since Ii degradation is a prerequisite for transport of MHC class II molecules
to the cell surface, these inhibitors are negative regulators of class II presentation (Amigorena
et al., 1995; Brachet et al., 1997; Neefjes and Ploegh, 1992). Naturally occurring protease
inhibitors exist as well. Cystatin is a reversible inhibitor of cysteine proteases like the
cathepsins. Cystatin family members are expressed in a tissue-specific manner and can
modulate cathepsin activities and thereby inhibit antigen presentation by MHC class II
molecules (Pierre and Mellman, 1998), although this is still somewhat controversial.
Pathogens are known to use a similar system to inhibit MHC class II presentation, as has
been reported for two filarial nematodes, Onchocerca volvulus and Acanthocheilonema viteae
(Hartmann et al., 1997; Schonemeyer et al., 2001). Both nematodes produce cystatin-like
molecules that have an immunosuppressive activity by inhibiting cathepsin S and L.
Moreover, Bm-CPI-2 is a cystatin homologue secreted by the parasite Brugia malayi that also
interferes with MHC class II processing by inhibiting multiple cysteine proteases (Manoury et
al., 2001).
II and HLA-DM (Zwart et al., 2005). Nature has thus developed a complicated system to
allow presentation of antigenic fragments generated in the endosomal track. It has also
developed multiple ways to manipulate this process, not only exploited by pathogens, but also
by tumours as will be discussed below.
MHC class II molecules in oncogenesis
Most tumours do not express MHC class II molecules. Exceptions are -obviously- B cell
leukemia like chronic lymphocytic leukemia, Burkitt lymphoma, EBV-induced B cell
Non-Hodgkin Lymphoma, follicular lymphoma and Kahler’s disease (Guy et al., 1986). In
addition, melanoma can express MHC class II molecules (Zeng et al., 2000), although often in
a rather heterologous manner, and Glioma type 1 tumours also constitutively express MHC
class II (Takamura et al., 2004). Furthermore, interferon J and possibly other factors can
induce MHC class II expression on Glioma type 2 and many other tumours including cervix
tumours (Santin et al., 1998) and bladder cancer (Champelovier et al., 2003). In most cases,
not only MHC class II molecules are expressed but also the accessory proteins required for
efficient transport (Ii) and peptide loading (HLA-DM) (Siegrist et al., 1995).
MHC class II-restricted presentation of exogenous antigens can easily be observed ex
vivo by EBV-transformed B cells (Nijenhuis et al., 1994) and melanoma cells (van Ham et al.,
2000) implying that the MHC class II system ‘works’ correctly and efficiently in these
tumours. In addition, MHC class II molecules can present ‘tumour-specific antigens’ like
Epstein Barr viral (EBV) antigen EBNA-1 (Voo et al., 2002) and melanoma-specific antigens
like tyrosinase and gp100 (Parkhurst et al., 2003; Topalian et al., 1994). Still, an efficient host
response is obviously lacking when a tumour appears and selective outgrowth of
tumour-specific CD4
+T cells has not been reported in patients, even though these T cells can be
expanded in vitro. Apparently tumour factors prevent expansion of these cells.
Interestingly, some tumours that express MHC class II also express inhibitors for the
MHC class II antigen presentation process. Most notably is the inhibitor for DM,
HLA-DO, in B cell leukemia. Whether this reflects a differentiation difference (HLA-DO is best
expressed in immature B cells) or an active attempt to inhibit antigen presentation by MHC
class II, is unclear. Other tumours secrete inhibitory cytokines like IL-10 to suppress MHC
class II and other responses, which is particularly clear for melanomas (Dummer et al., 1996)
and EBV-induced B cell tumours (Benjamin et al., 1992). The EBV genome encodes a
homologous protein for IL-10 (BCRF1; (Moore et al., 1991; Vieira et al., 1991)) that may
also inhibit T cell responses, although this is not fully established. Other tumours, like
neuroblastoma, actively down regulate expression of MHC class II by silencing the CTIIA
promoter (Croce et al., 2003).
Patients selectively lacking expression of MHC class II molecules (and not MHC class I)
exist. These bare lymphocyte syndrome patients usually have genetic defects in the
transcription machinery regulating expression of MHC class II molecules and its accessory
proteins HLA-DM and the invariant chain (Mach et al., 1994). Defects have been reported for
the transcription factor CIITA (Steimle et al., 1993). Although these patients are prone to
many infections, no increased rate of tumour formation has been reported. Similarly, no
increased tumour incidence is observed in mice deficient for MHC class II molecules, DM or
Ii. These observations suggest that class II plays no active role in the tumour formation.
responses (Ossendorp et al., 1998). These are most likely not the MHC class II molecules
expressed on tumours but merely MHC class II molecules expressed on professional antigen
presenting cells, like DCs. These cells probably internalise apoptotic bodies or necrotic debris
from tumour cells and present fragments to the CD4
+T cells, which then stimulate cytotoxic
T cell proliferation (Ossendorp et al., 1998). State of the art tumour vaccination strategies
therefore include -beside antigens for MHC class I molecules- antigens for presentation by
MHC class II molecules. These antigens can be targeted into the MHC class II pathway using
Fc-receptor-mediated uptake (You et al., 2001), via the mannose receptor (van Bergen et al.,
1999), or (although this pathway is more undefined) directly used in the form of exosomes
(Zitvogel et al., 1998). The stimulation of both the MHC class I and MHC class II pathway
may ensure a better stimulation of tumour-specific cytotoxic T cells, and thus a better
anti-tumour response.
Concluding remarks
Most attention in immunotherapy of cancer has been on MHC class I molecules, but the
concepts with respect to the source of targets (antigens) is very similar for MHC class II
molecules. In fact, using antigen presentation by MHC class II may even have a number of
profound advantages. First of all, any therapy is more selective since MHC class II molecules
are only expressed on a restricted number of tissues. In addition, delivery systems for
antigenic fragments to MHC class II molecules are considerably simpler compared to MHC
class I. Antigens do not have to be delivered into the cytoplasm but simply opsonised to enter
the endocytic track for efficient loading onto MHC class II. Finally, whereas MHC class I
molecules interact only with short peptides that do not allow further modifications, MHC
class II molecules bind peptides in a different way, as peptides associated to MHC class II
molecules extent out of the peptide-binding groove (Stern et al., 1994). Modifications can
safely be introduced in these extensions without affecting the immunogenicity. Yet, the
pharmacodynamics and stability of the peptides can be strongly affected. However, these
modifications do allow further improvement in targeting the peptides to the correct cells by
using for example the mannose receptor on DCs (Tan et al., 1997), and may be critical for
mounting an efficient and successful immune response against tumours.
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