laboratory of dendritic cell biology, department of ... · 1868 discovery of langerhans’ cells in...
TRANSCRIPT
Den
driti
c ce
lls:
Mas
ter s
witc
hes
of im
mun
ity
Prof
. D
r. D
iana
Dud
ziak
Labo
rato
ry o
f D
endr
itic
Cel
l Bio
logy
, D
epar
tmen
t of
Der
mat
olog
y, E
rlan
gen,
Ger
man
y
dian
a.du
dzia
k@uk
-erlan
gen.
de
Ant
igen
pre
sent
ing
cells
Mak
roph
ages
Mon
ocyt
es
Den
driti
c ce
lls
B ce
lls
!tre
e lik
e cy
topl
asm
ext
ensi
ons
(lat.
dend
ritic
us)
!18
68 d
isco
very
of L
ange
rhan
s’ce
lls in
ski
n
!fu
nctio
nal d
isco
very
of D
Cs
by R
alph
M. S
tein
man
, 197
3 (N
obel
priz
e, 2
011)
!ve
ry im
porta
nt a
ntig
en p
rese
ntin
g ce
lls
!br
idge
inna
te a
nd a
cqui
red
imm
unity
Den
driti
c ce
lls (D
Cs)
!tre
e lik
e cy
topl
asm
ext
ensi
ons
(lat.
dend
ritic
us)
!18
68 d
isco
very
of L
ange
rhan
s’ce
lls in
ski
n
!fu
nctio
nal d
isco
very
of D
Cs
by R
alph
M. S
tein
man
, 197
3 (N
obel
priz
e, 2
011)
!ve
ry im
porta
nt a
ntig
en p
rese
ntin
g ce
lls
!br
idge
inna
te a
nd a
cqui
red
imm
unity
!ne
eded
for i
nitia
tion
of C
D4
and
CD
8 T
cell
resp
onse
s
!bu
t als
o ne
eded
for m
aint
enan
ce o
f per
iphe
ral t
oler
ance
Den
driti
c ce
lls (D
Cs)
1.Lo
caliz
atio
n
2.An
tigen
upt
ake
and
antig
en p
roce
ssin
g
3.D
C m
atur
atio
n an
d m
igra
tion
4.An
tigen
pre
sent
atio
n
5.T
cell
activ
atio
n
6.W
hat m
akes
DC
s so
com
plic
ated
?
Den
driti
c ce
lls (D
Cs)
1.Lo
caliz
atio
n
2.An
tigen
upt
ake
and
antig
en p
roce
ssin
g
3.D
C m
atur
atio
n an
d m
igra
tion
4.An
tigen
pre
sent
atio
n
5.T
cell
activ
atio
n
6.W
hat m
akes
DC
s so
com
plic
ated
?
Den
driti
c ce
lls (D
Cs)
Loca
lizat
ion
of d
endr
itic
cells
Brai
n
Tons
il
Thym
us
Lym
phno
des
Skin
Bone
mar
row
Sple
en
Inte
stin
e
Muc
osa
Muc
osa
Loca
lizat
ion
of d
endr
itic
cells
Brai
n
Tons
il
Thym
us
Lym
phno
des
Skin
Bone
mar
row
Sple
en
Inte
stin
e
Muc
osa
Muc
osa
Lind
quis
t et a
l., N
at. I
mm
unol
. (20
04);
Shak
hare
t al.,
200
5
Velo
city
: B Z
one
>Sub
caps
ular
DC
s >
Perif
ollic
ular
> T
Zone
Gre
en D
Cs
C57
BL/6
tran
sgen
ic
CD
11c
Prom
oter
::EY
FP m
ouse
Diff
eren
tial l
ocal
izat
ion
and
activ
ity o
f den
driti
c ce
lls in
lym
ph n
odes
Intra
vital
2-Ph
oton
mic
rosc
opy
1.Lo
caliz
atio
n
2.An
tigen
upt
ake
and
antig
en p
roce
ssin
g
(cla
ssic
al /
alte
rnat
ive
proc
essi
ng)
3.D
C m
atur
atio
n an
d m
igra
tion
4.An
tigen
pre
sent
atio
n
5.T
cell
activ
atio
n
6.W
hat m
akes
DC
s so
com
plic
ated
?
Den
driti
c ce
lls (D
Cs)
Ant
igen
s
!ba
cter
ial p
rote
ins
!vi
ral p
rote
ins
!tu
mor
mat
eria
l
!ap
opto
tic/n
ecro
tic m
ater
ial
!im
mun
e co
mpl
exes
(IgG
-ant
igen
)
!lip
ids
Phag
ocyt
osis
:-P
artic
le (>
Ø1μ
m)
-mem
bran
e ex
trusi
ons
(pse
udop
odex
tens
ion)
,
-Act
in a
ssem
blin
g (C
DC
42, R
ac)
Ant
igen
upt
ake
Mac
ropi
nozy
tosi
s:-c
onst
itutiv
e pr
oces
s-a
ctin
-med
iate
d m
embr
ane
inva
gina
tion
-upt
ake
of e
xtra
cellu
lar f
luid
s an
d so
lubl
e an
tigen
s
Ant
igen
upt
ake
Addi
tiona
l info
rmat
ion:
Trom
betta
and
Mel
lman
Annu
.Rev
.Imm
unol
. 200
5
Ant
igen
upt
ake
Rec
epto
r-med
iate
d en
docy
tosi
s:-u
ptak
e in
to c
lath
rin-c
oate
d ve
sicl
es-‘
coat
ed p
its’
-fun
ctio
n of
cav
eolin
-coa
ted
vesi
cles
unk
nown
1.Lo
caliz
atio
n
2.An
tigen
upt
ake
and
antig
en p
roce
ssin
g
(cla
ssic
al M
HC-
I / a
ltern
ativ
epr
oces
sing
)
3.D
C m
atur
atio
n an
d m
igra
tion
4.An
tigen
pre
sent
atio
n
5.T
cell
activ
atio
n
6.W
hat m
akes
DC
s so
com
plic
ated
?
Den
driti
c ce
lls (D
Cs)
Ant
igen
pro
cess
ing
in th
e co
ntex
t of M
HC
I
!de
grad
atio
nof
cel
lula
rorv
iral
antig
ens
in th
epr
otea
som
!TA
P-tra
nspo
rtert
rans
ports
antig
enin
toen
dopl
asm
atic
retic
ulum
(ER
)
!an
tigen
-load
ing
of M
HC
-cla
ssI
mol
ecul
es
!tra
nspo
rtof
pep
tid-M
HC
I-com
plex
esvi
a G
olgi
netw
ork
to th
ece
llsu
rface
Trom
betta
and
Mel
lman
Annu
. Rev
. Im
mun
ol.,
2005
Ant
igen
sou
rces
for M
HC
cla
ss I
1.cy
toso
lic p
rote
ins
2.al
tern
ativ
e tra
nscr
ipts
and
defe
ctiv
e pr
otei
ns (D
RiP
s)3.
prot
eins
der
ived
from
ER
4.en
docy
tose
d pr
otei
ns
trans
ferre
d in
to th
e cy
topl
asm
5.en
docy
tose
d pr
otei
ns lo
aded
in
endo
som
es to
recy
clin
g M
HC
I
Ant
igen
sou
rces
for M
HC
cla
ss I
DRiP
s:
1.(d
efec
tive rib
osom
al p
rodu
cts)
2.sh
ort l
ived
pro
tein
s,
non-
com
plet
e pr
otei
ns,
wron
gly
fold
ed3.
self
and
vira
l pep
tides
4.
intra
cellu
larly
pro
duce
d
Yewd
ell,
JI, 1
996
Trom
betta
and
Mel
lman
Annu
. Rev
. Im
mun
ol.,
2005
Ant
igen
sou
rces
for M
HC
cla
ss I
Labe
ling
of p
rote
ins
that
nee
d to
be
deg
rade
d:
1.U
biqu
itin
(Ub)
, 76
aa, 8
kD
a2.
E1, E
2, E
3 Ub
-liga
ses
invo
lved
in
ubiq
uitin
atio
n of
Lys
ine
resi
dues
of
mol
ecul
es th
at n
eed
to b
e de
grad
ed
Trom
betta
and
Mel
lman
Annu
. Rev
. Im
mun
ol.,
2005
Ant
igen
sou
rces
for M
HC
cla
ss I
Prot
easo
me:
1.2M
Da,
15n
m lo
ng, 1
1nm
, 30.
000
per
cell
2.ce
ntra
l gar
bage
can
(20
S-co
re),
two
19 S
-cap
ping
com
plex
es3.
20 S
Cor
e:R
ing
of e
ach
7α-,
and β-
subu
nits
(αββα)
, mul
ticat
alyt
icpr
otei
nase
4.ß1
i (LM
P2)
-low
PG
PH-a
ctiv
ity (c
leav
age
af
ter a
cidi
c aa
)ß2
i (M
ECL-
1)-t
rypt
icac
tivity
(cle
avag
e af
ter
alka
line
aa)
ß5i (
LMP7
)-c
hym
otry
ptic
activ
ity (c
leav
age
afte
r hyd
roph
obic
aa)
Trom
betta
and
Mel
lman
Annu
. Rev
. Im
mun
ol.,
2005
PGPH
: pep
tidylg
luta
myl
pept
ide
hydr
olyz
ing
Ant
igen
sou
rces
for M
HC
cla
ss I
Prot
easo
me:
1.ub
iqui
tinat
edpr
otei
n bi
nds
to 1
9S-
com
plex
2.U
bwi
ll be
cle
aved
, ATP
-de
pend
ent
3.pr
otei
ns u
nfol
d4.
prot
ease
s on
the
activ
e ce
nter
s of
th
e β-
subu
nits
cle
ave
prot
eins
in
10-2
0 aa
pept
ides
5.fu
rther
cle
avag
e by
cyt
osol
ic
pept
idas
es
Trom
betta
and
Mel
lman
Annu
. Rev
. Im
mun
ol.,
2005
MH
C c
lass
I an
tigen
pro
cess
ing
Abel
e an
d Ta
mpé
FEBS
Let
ters
, 200
6
MH
C c
lass
I an
tigen
pro
cess
ing
8-10
aa
Abel
e an
d Ta
mpé
FEBS
Let
ters
, 200
6
MH
C c
lass
I an
tigen
pro
cess
ing
8-10
aa
Abel
e an
d Ta
mpé
FEBS
Let
ters
, 200
6
TAP
tran
spor
ter
-TAP
tran
spor
ter (
Tran
spor
ter a
ssoc
iate
d wi
th A
ntig
en P
roce
ssin
g)
with
ATP
-bin
ding
cas
sette
(ABC
-tran
spor
ter)
-tra
nspo
rt of
cle
aved
pro
tein
frag
men
ts/p
eptid
es fr
om c
ytos
ol in
to E
R
-loc
aliz
ed in
ER
and
cis
-Gol
gi)
Abel
e an
d Ta
mpe
lFE
BS L
ette
rs, 2
006
-upr
egul
ated
by
IFN
-γ, s
tabi
lizat
ion
of th
e co
mpl
ex-i
n tu
mor
s lo
w TA
P ac
tivity
-het
erod
imer
of T
AP1
(748
aa) a
nd T
AP2
(686
aa)
-TM
-dom
ain
with
pep
tide
bind
ing
side
-cyt
osol
ic n
ucle
otid
e-bi
ndin
g do
mai
n (N
BD) –
-tra
nspo
rt of
8-1
6 an
d 8-
12 a
aTAP
tran
spor
ter
Abel
e an
d Ta
mpe
lFE
BS L
ette
rs, 2
006
Vira
l Int
erfe
renc
e w
ith T
AP
tran
spor
ter
!M
odul
atio
n of
TAP
func
tion
by v
iral f
acto
rs. U
pper
pan
el: T
he
stru
ctur
al o
rgan
izatio
n of
the
pept
ide-
load
ing
com
plex
(PLC
) is
illu
stra
ted
as a
mod
el. E
Rp5
7 is
cov
alen
tly li
nked
to ta
pasin
via a
disu
lfide
bond
(C95
of t
apas
in to
the
Cxx
Cm
otif
of th
e ox
idor
educ
tase
).
!W
ithin
the
ER q
ualit
y co
ntro
l, ca
lretic
ulin
reco
gniz
es th
e N
-co
re g
lycos
ylatio
n of
the
MH
C I
heav
y ch
ain
(hc)
and
form
s ad
ditio
nal c
onta
cts
with
ERp
57. F
or s
impl
icity
, onl
y on
e of
fo
ur T
AP-a
ssoc
iate
d su
b-co
mpl
exes
(tap
asin
, MH
C h
eavy
ch
ain,
b2m
, ERp
57 a
nd c
alre
ticul
in) i
s sh
own.
!Th
e E1
9 pr
otei
n of
ade
novi
rus
E3di
stur
bsth
e in
tera
ctio
n of
MH
C c
lass
Im
olec
ules
with
the
pre-
asse
mbl
ed T
AP–
tapa
sin–
ERp5
7co
mpl
ex w
hich
impa
irs e
fficie
nt p
eptid
e lo
adin
g of
MH
C c
lass
I.
!M
iddl
e pa
nel:
The
mK3
pro
tein
of m
urin
e c-
herp
esvi
rus-
68bi
nds
dire
ctly
to T
APan
d in
duce
spo
lyub
iqui
tyla
tion
and
subs
eque
ntly
prot
easo
mal
degr
adat
ion.
!Th
e in
tera
ctio
n of
UL4
9.5
of th
e bo
vine
her
pes
viru
sdr
ives
TA
P to
pro
teas
omal
degr
adat
ion
and
arre
sts
TAP
in a
tra
nspo
rt-in
com
pete
nt c
onfo
rmat
ion,
in w
hich
bin
ding
of A
TP
and
pept
ide
is n
ot a
ffect
ed.
!Lo
wer p
anel
: IC
P47
of th
e he
rpes
sim
plex
viru
sin
hibi
ts
pept
ide
bind
ing
from
the
cyto
solic
site
of T
AP.
!Th
e as
socia
tion
of U
S6 o
f the
hum
an c
ytom
egal
oviru
sto
th
e ER
-lum
inal
tran
smem
bran
e co
re o
f TAP
blo
cks
ATP
bind
ing
to th
e cy
toso
lic p
eptid
e lo
adin
g co
mpl
ex.
Pept
ide
load
ing
com
plex
(PLC
)
-TAP
-/-m
ice
-pep
tide
trans
port
into
ER
blo
cked
-no
(few)
MH
C-I-
pept
id-c
ompl
exes
on
the
surfa
ce
-mul
ti-co
mpo
nent
-pep
tide-
load
ing-
com
plex
(PLC
) -T
AP h
eter
odim
er-4
mol
ecul
es ta
pasi
n (T
AP-b
indi
ng p
rote
in=
TAP-
BP) a
nd
-4 m
olec
ules
MH
C-c
lass
-I -l
ectin
-like
cha
pero
ns: C
alre
ticul
in, C
alne
xin,
Oxid
ored
ucta
se E
Rp5
7
β βββ2 m
icro
glob
ulin
-ess
entia
l for
tran
spor
t of M
HC
I to
the
cell
surfa
ce
-sta
biliz
es p
eptid
es in
MH
CI-b
indi
ng g
rove
-i
s β2
M m
issi
ng -
low
to n
o M
HC
I mol
ecul
es o
n th
e su
rface
-d
evel
opm
ent o
f CD
8 T
cells
dis
tract
ed-β
2m n
ot p
olym
orph
-lat
eral
ly to
α3
subu
nits
of M
HC
-I (a
lso
in C
D1,
non
-cla
ssic
al M
HC-
mol
ecul
es),
-no
TM-d
omai
n
β βββ2 m
icro
glob
ulin
Abel
e an
d Ta
mpé
FEBS
Let
ters
, 200
6
!pe
ptid
e-M
HC
I-com
plex
tran
sfer
red
from
ER
via
se
cret
ory
path
way
into
Gol
gi n
etwo
rk to
cel
l su
rface
!po
st-tr
ansl
atio
nal m
odifi
catio
ns o
f MH
CI (
N-
Glyc
an-B
indi
ng in
ER
and
Gol
gi)
!in
tera
ctio
n of
Pep
tide-
MH
CI-c
ompl
ex w
ith T
CR
of
CD
8 T
cells
Tran
spor
t of p
eptid
e M
HC
I com
plex
to s
urfa
ce Abel
e an
d Ta
mpé
FEBS
Let
ters
, 200
6
Sum
mar
y: A
ntig
en p
roce
ssin
g fo
r MH
CI
1. P
rote
ins
with
mis
take
s ar
e so
urce
of M
HC
I ant
igen
s2.
Wro
ngly
fold
ed p
rote
ins
labe
led
with
Ub
3. D
egra
datio
n of
Ub-
labe
led
prot
eins
in p
eptid
es in
pro
teas
om, f
urth
er tr
imm
ing
to s
horte
r pep
tide
by c
ytos
olic
pep
tidas
es4.
Pep
tides
tran
spor
ted
into
ER
by
TAP-
com
plex
, fur
ther
trim
min
g of
pep
tides
to 8
-10
aa5.
Pep
tides
load
ed o
nto
MH
C-I
by p
eptid
e-lo
adin
g co
mpl
ex (P
LC) c
onsi
stin
g of
ERp
57, T
apas
in, a
nd C
alre
ticul
in6.
pM
HC
-I co
mpl
ex tr
ansf
erre
d to
sur
face
via
Gol
gi n
etwo
rk
Vyas
, Nat
Rev
.Imm
unol
, 200
8
1.Lo
caliz
atio
n
2.An
tigen
upt
ake
and
antig
en p
roce
ssin
g
(cla
ssic
al M
HC-
II / a
ltern
ativ
epr
oces
sing
)
3.D
C m
atur
atio
n an
d m
igra
tion
4.An
tigen
pre
sent
atio
n
5.T
cell
activ
atio
n
6.W
hat m
akes
DC
s so
com
plic
ated
?
Den
driti
c ce
lls (D
Cs)
!in
tern
aliz
atio
nof
ant
igen
s
(rece
ptor
-med
iate
den
docy
tosi
s)
!pr
oteo
lysi
sin
lyso
som
(cle
avag
eof
thio
l gro
ups)
!tra
nspo
rtof
pep
tides
in s
o ca
lled
MIIC
com
plex
es
MH
C c
lass
II a
ntig
en p
roce
ssin
g
Org
anel
les
of th
e en
docy
tic p
athw
ay
!re
cept
or-re
cycl
ing
from
1-2
min
until
up
to 2
0-30
min
!In
tern
aliz
atio
n in
to e
arly
endo
som
es, l
ate
endo
som
es, a
nd
lysos
omes
!pH
dro
ps, l
ysos
omal
hyd
rola
se-
activ
ity in
crea
ses
the
deep
er th
e
carg
o is
tran
spor
ted
into
the
cell
!la
te e
ndos
omes
and
lyso
som
es
are
in e
xcha
nge
!re
gene
ratio
n of
lyso
som
es
Trom
betta
and
Mel
lman
Annu
. Rev
. Im
mun
ol.,
2005
!G
ILT:
gam
ma-
Inte
rfero
n-in
duci
ble
lyso
som
ale
Thio
l-Red
ucta
se!
activ
e at
ver
y lo
w pH
,!
clea
ves
disu
lfide
-brid
ges
Lyso
som
al th
iol r
educ
tase
GIL
T
Li e
t al.,
Im
mun
ol. R
ev. 2
005
MHC
II-CL
IP
MH
C c
lass
II a
ntig
en p
roce
ssin
g
!M
HC
II bl
ocke
dby
inva
riant
chai
nli
!AE
P an
d C
athe
psin
escl
eave
inva
riant
cha
inN
and
C te
rmin
ally
resu
lting
in M
HC
II-C
lipco
mpl
ex
!ch
aper
onH
LA-D
M e
xcha
nges
the
CLI
P fra
gmen
tint
oan
tigen
icpe
ptid
es
!tra
nspo
rtof
pM
HC
IIco
mpl
exto
su
rface
!ch
arac
teris
ticfo
rpro
fess
iona
lan
tigen
pres
entin
gce
lls
1.Lo
caliz
atio
n
2.An
tigen
upt
ake
and
antig
en p
roce
ssin
g
(cla
ssic
al/ a
ltern
ativ
e pr
oces
sing
-cr
oss-
pres
enta
tion)
3.D
C m
atur
atio
n an
d m
igra
tion
4.An
tigen
pre
sent
atio
n
5.T
cell
activ
atio
n
6.W
hat m
akes
DC
s so
com
plic
ated
?
Den
driti
c ce
lls (D
Cs)
Cal
nexi
nC
alre
ticul
inER
p57
Sec6
1
TAP-
1TA
P-2
Tapa
sin
{
AEP
Cys
tatin
C
Cat
S et
c.H
2-D
M
Gilt
H2-
DO
ERAA
P
Cros
spr
esen
tatio
nG
olgi
Alte
rnat
ive
MHC
I and
MHC
II an
tigen
pro
cess
ing
path
way
s
Antig
en c
ross
pre
sent
atio
n
!an
tigen
upta
kevi
a re
cept
orm
edia
ted
endo
cyto
sis
into
the
so c
alle
dph
agos
ome/
phag
olys
osom
e
!up
take
nan
tigen
sre
ach
the
cyto
sol
(unc
lear
mec
hani
sm)
!de
grad
atio
nof
sel
fand
ode
r vira
lpr
otei
ns/a
ntig
ens
in th
epr
otea
som
e
!In
ER
: loa
ding
of p
eptid
esto
MH
C-I
!tra
nspo
rtof
pep
tid-M
HC
-com
plex
esvi
a G
olgi
-net
work
to th
esu
rface
Trom
betta
and
Mel
lman
Annu
. Rev
. Im
mun
ol.,
2005
Antig
en c
ross
pre
sent
atio
n
!Cr
oss-
pres
enta
tion:
= lo
adin
g ex
ogen
ous
antig
ens
onto
MH
C-I
= m
echa
nism
s st
ill un
clea
r
Antig
en c
ross
pre
sent
atio
n –
Hyp
othe
sis
1
1.
Trom
betta
and
Mel
lman
Annu
. Rev
. Im
mun
ol.,
2005
!H
ypot
hesi
s 1:
!ph
ysic
al d
isru
ptio
n of
en
doso
mal
/lyso
som
al m
embr
anes
!an
tigen
reac
hes
cyto
plas
m
Antig
en c
ross
pre
sent
atio
n –
Hyp
othe
sis
2
2.
Trom
betta
and
Mel
lman
Annu
. Rev
. Im
mun
ol.,
2005
!H
ypot
hesi
s 2:
!re
trogr
ade
antig
en tr
ansp
ort
endo
som
e →
Gol
gi →
ER
!sp
ecul
ated
tra
nslo
catio
n ch
anne
l -tra
nspo
rt of
ant
igen
from
ER
into
cy
topl
asm
3.
Trom
betta
and
Mel
lman
Annu
. Rev
. Im
mun
ol.,
2005
Antig
en c
ross
pre
sent
atio
n –
Hyp
othe
sis
3
3.
!H
ypot
hesi
s 3:
!ph
agos
omes
fuse
with
ER
Cyt
osol
ic a
nd v
acuo
lar p
athw
ay
Joffr
e, 2
012
TAP
depe
nden
tTA
Pin
depe
nden
t
1.Lo
caliz
atio
n
2.An
tigen
upt
ake
and
antig
en p
roce
ssin
g
(cla
ssic
al M
HC
-I /a
ltern
ativ
epr
oces
sing
-au
toph
agy)
3.D
C m
atur
atio
n an
d m
igra
tion
4.An
tigen
pre
sent
atio
n
5.T
cell
activ
atio
n
6.W
hat m
akes
DC
s so
com
plic
ated
?
Den
driti
c ce
lls (D
Cs) Yo
shin
oriO
hsum
i
Auto
phag
y: P
rese
ntat
ion
of e
ndog
enou
s an
tigen
s on
MHC
II
Vyas
, Nat
Rev
.Imm
unol
, 200
8
!Au
toph
agy:
!
auto
phag
yis
a p
roce
ss, i
n wh
ich
mem
bran
es a
ssem
ble
de
novo
!pr
esen
tatio
n of
end
ogen
ous
antig
ens
on M
HC
-Kla
sse-
II !
path
ogen
s, s
elf p
rote
ins
!m
atur
atio
n of
the
phag
osom
eby
TLR
act
ivat
ion
(viru
s,
bact
eria
)!
fusi
on o
f the
pha
goso
me
with
lys
osom
e→
Phag
olys
osom
e!
antig
en lo
adin
g on
to M
HC
cla
ss
II in
the
lysos
ome
!m
icro
-and
mac
roau
toph
agy
1.Lo
caliz
atio
n
2.An
tigen
upt
ake
and
antig
en p
roce
ssin
g
(cla
ssic
al M
HC
-I / a
ltern
ativ
e pr
oces
sing
)
3.DC
mat
urat
ion
and
mig
ratio
n
4.An
tigen
pre
sent
atio
n
5.T
cell
activ
atio
n
6.W
hat m
akes
DC
s so
com
plic
ated
?
Den
driti
c ce
lls (D
Cs)
Patte
rn re
cogn
ition
rece
ptor
s re
spon
sibl
e fo
r sen
sing
Extra
cellu
lar P
RRs:
!To
ll-lik
e re
cept
ors
(TLR
s)!
C-T
ype
lect
in re
cept
ors
(CLR
s)!
Scav
enge
r rec
epto
rs
Intra
cellu
lar P
RR
s
!N
OD
-like
rece
ptor
s (N
LRs)
!R
IG-I-
like
prot
eins
Path
ogen
-Ass
ocia
ted
Mol
ecul
ar P
atte
rns
Defin
ition
:
!“P
atte
rn R
ecog
nitio
n R
ecep
tors
”rec
ogni
ze s
truct
ures
spe
cific
ally
co
nser
ved
in m
icro
orga
nism
s, s
o-ca
lled
‘Pat
hoge
n-As
soci
ated
M
olec
ular
Pat
tern
s’(P
AMPs
)
!Si
gnal
tran
sduc
tion
via
Patte
rn R
ecog
nitio
n R
ecep
tors
in a
ntig
enpr
esen
ting
cells
lead
s to
-cyt
okin
e pr
oduc
tion
(pro
infla
mm
ator
y:TN
Fα, I
L6, I
L12,
an
ti-in
flam
mat
ory:
IL-1
0, T
GFβ
)-c
hem
okin
e pr
oduc
tion
(CC
R7)
-upr
egul
atio
n of
co-
stim
ulat
ory
mol
ecul
es (C
D80
, CD
86)
!st
ate
of a
ctiv
atio
n an
d an
tigen
pre
sent
atio
n co
nnec
t the
inna
te w
ith th
e ad
aptiv
e im
mun
e sy
stem
Rec
ogni
tion
of p
atho
gens
by
Toll
like
rece
ptor
s (T
LRs)
"re
cogn
ition
of s
truct
ural
ly c
onse
rved
m
olec
ules
der
ived
from
mic
robe
s (P
AMPs
)
"si
gnal
ing
via
MyD
88 o
r TR
IF
"ac
tivat
ion
of N
FκB
and
IRFs
"pa
thog
en-s
peci
fic re
spon
se(c
ytok
ine
prod
uctio
n, c
ell r
ecru
itmen
t)
Pam
3lip
opep
tides
LPS
Flag
ellin
Zym
osan
lipop
eptid
es
dsR
NA
pIC
ssR
NA
R84
8
ssR
NA
R84
8
CpG
DN
A
Pept
ido-
glyc
an
Imm
atur
e an
d m
atur
e D
Cs
!DC
s in
the
perip
hery
sho
w a
n im
mat
ure
phen
otyp
e:-s
entin
els
-hig
h an
tigen
upt
ake
and
proc
essi
ng c
apac
ity-o
nly
low
leve
ls o
f co-
stim
ulat
ory
mol
ecul
es-o
nly
low
leve
ls o
f MH
C-I
and
MH
C-II
on
the
cell
surfa
ce
!Up
on s
timul
atio
n, D
Cs m
igra
te fr
om p
erip
hery
into
loca
l lym
ph n
odes
-red
uced
ant
igen
upt
ake
capa
city
-stro
ng a
ntig
en p
rese
ntat
ion
of p
eptid
e-M
HC
-com
plex
-cyt
okin
e se
cret
ion,
upr
egul
atio
n of
co-
stim
ulat
ory
mol
ecul
es a
nd C
CR
7-s
trong
inte
ract
ion
with
T c
ells
!Di
stin
ctio
n of
con
vent
iona
l tis
sue
resi
dent
(sem
i mat
ure)
and
mig
rato
ry
DCs,
as
wel
l as
plas
mac
ytoi
d DC
s
1.Lo
caliz
atio
n
2.An
tigen
upt
ake
and
antig
en p
roce
ssin
g
(cla
ssic
al M
HC
-I / a
ltern
ativ
e pr
oces
sing
)
3.D
C m
atur
atio
n an
d m
igra
tion
4.An
tigen
pre
sent
atio
n
5.T
cell
activ
atio
n
6.W
hat m
akes
DC
s so
com
plic
ated
?
Den
driti
c ce
lls (D
Cs)
The
imm
unol
ogic
al s
ynap
se
-Upr
egul
atio
n of
co-
stim
ulat
ory
mol
ecul
es (C
D80
/CD
86, I
g-su
perfa
mily
)
The
imm
unol
ogic
al s
ynap
se
Supr
amol
ecul
arac
tivat
ion
com
plex
(SM
AC)
cent
ral,
perip
hera
l, di
stal
Yan
Yu e
t al.
J Ce
ll Sc
i 201
3;12
6:10
49-1
058
Sign
al 1
(ant
igen
), Si
gnal
2 (c
o-st
imul
atio
n),
Sign
al 3
(cyt
okin
es/T
cel
l pol
ariz
atio
n)
Kaps
enbe
rg
Sign
al 1
(ant
igen
), Si
gnal
2 (c
o-st
imul
atio
n),
Sign
al 3
(cyt
okin
es/T
cel
l pol
ariz
atio
n)
Cyt
okin
ean
d ch
emok
ine
prod
uctio
nst
rong
lyde
pend
on th
egi
ven
stim
ulus
Cyt
okin
es: (
secu
red)
: IL-
12 n
eces
sary
forT
H1 C
D4
T ce
llpo
lariz
atio
n,
TGF-β
nece
ssar
yfo
rTre
gpo
lariz
atio
nKa
psen
berg
1.Lo
caliz
atio
n
2.An
tigen
upt
ake
and
antig
en p
roce
ssin
g
(cla
ssic
al M
HC
-I / a
ltern
ativ
e pr
oces
sing
)
3.D
C m
atur
atio
n an
d m
igra
tion
4.An
tigen
pre
sent
atio
n
5.T
cell
activ
atio
n
6.W
hat m
akes
DC
s so
com
plic
ated
?
Den
driti
c ce
lls (D
Cs)
Antig
en lo
aded
DCs
inte
ract
with
ant
igen
spe
cific
T c
ells
inde
pend
ent o
f the
DC
mat
urat
ion
stat
us
Shak
aret
al.,
Nat
. Im
mun
ol. (
2005
)
EYFP
-DC
CFP
-T tr
acks
GFP
-OTI
Itra
cks
tole
roge
nic
(-CD
40)
imm
unog
enic
(+C
D40
)
DC
s di
rect
T c
ell p
olar
izat
ion
?
1.Lo
caliz
atio
n
2.An
tigen
upt
ake
and
antig
en p
roce
ssin
g
(cla
ssic
al M
HC
-I / a
ltern
ativ
e pr
oces
sing
)
3.D
C m
atur
atio
n an
d m
igra
tion
4.An
tigen
pre
sent
atio
n
5.T
cell
activ
atio
n
6.W
hat m
akes
DCs
so
com
plic
ated
?-
Very
sm
all c
ell n
umbe
rs,
-C
omes
in a
var
iety
of s
ubse
ts, l
ocal
ized
in d
iffer
ent t
issu
es-
Can
eas
ily a
ctiva
te v
ia p
repa
ratio
n fro
m ti
ssue
-Va
riety
of s
urfa
ce m
arke
rs
Den
driti
c ce
lls (D
Cs)
Den
driti
c ce
lls (D
Cs)
Liu
K, S
cien
ce. 2
009
Apr 1
7;32
4(59
25):3
92-7
.
MP:
mye
loid
prog
enito
rM
DP:
mac
roph
age
and
DC
pre
curs
orC
DP:
com
mon
DC
pre
curs
orPr
eD
C:
prec
urso
rsof
cD
Cs
Tip-
DC
s: T
NF
indu
cibl
eni
tric
oxid
esy
ntha
se(iN
OS)
-pro
duci
ngD
Cs
New
cla
ssifi
catio
n of
DC
sub
popu
latio
ns
Gul
liam
s, N
at. R
ev. I
mm
unol
, 201
4
His
tocy
tom
etry
of D
C s
ubpo
pula
tions
Ger
ner,
Imm
unity
, 201
2
CD
11ch
igh
CD
8-C
D11
b+
CD
11ch
igh
CD
8+C
D4-
CD
11b-
(‘lym
phoi
d’)
CD
11clo
w
B220
+
GR
1+PD
CA-
1+Si
glec
H+
plas
mac
ytoi
d
Sple
enLy
mph
nod
ePe
yer’s
Patc
hTh
ymus
Live
r
CD
11c+
CD
8int
Lang
erin
+
CD
103+
CD
11c+
Lang
erin
+
Epca
m+
CD
103-
CD
11b+
Lang
erha
ns’c
ells
Skin
drai
ning
LN
Der
mis
Epid
erm
is
CD
11c+
Lang
erin
+
CD
103+
CD
11c+
Lang
erin
+
CD
103-
CD
11c+
Lang
erin
-
CD
11b-
Furth
erdi
stin
ctio
nof
DC
sub
popu
latio
ns in
lam
ina
prop
ria, l
ung,
thym
us…
CD
8-C
D4-
CD
8-C
D4+
Res
iden
t DC
s
(mye
loid
)
CD
11c+
Lang
erin
-
CD
11bH
igh
CD
207+
DD
CC
D20
7-D
DC
Mig
rato
ry L
C
Org
an d
istr
ibut
ion
of m
urin
e D
endr
itic
cells
CD
207+
mLC
s
Mur
ine
resi
dent
CD
8+D
Cs
!cr
oss-
pres
enta
tion
of e
ndoc
ytos
ed a
ntig
ens
on
MH
CI
!ac
tivat
ion
of C
D8+
cyto
toxic
T c
ells
(lea
ding
to IF
N-
γ, G
ranz
yme)
!al
so a
ble
to a
ctiv
ate
T H1
CD
4+he
lper
T c
ells
(IFN
-γ)
, by
antig
en p
rese
ntat
ion
on M
HC
II!
upta
ke o
f tum
or m
ater
ial,
viru
s-in
fect
ed c
ells
!m
ain
prod
ucer
s of
IL-1
2!
addi
tiona
l rec
epto
rs: D
EC20
5, X
CR
-1, C
lec9
A!
BATF
3 de
pend
ent
!C
ross
-pre
sent
atio
n de
mon
stra
ted
also
for s
ome
CD
103+
mig
rato
ry D
Cs
CD
11ch
igh
CD
8+/C
D11
b-
(‘lym
phoi
d’)
Mur
ine
resi
dent
CD
8-D
Cs
!im
porta
nt fo
r ant
i-bac
teria
l, an
ti-pa
rasi
te im
mun
e re
spon
se
!up
take
of ‘
Bloo
d-bo
rn A
ntig
ens’
!an
tigen
pre
sent
atio
n on
MH
C-c
lass
II
!ac
tivat
ion
of T
H2
CD
4+T-
help
er c
ells
(IL-
4)
!up
regu
latio
n an
d se
cret
ion
of N
otch
-liga
nds
!fu
rther
rece
ptor
s: D
CIR
2, S
IRPα
!IR
F4 d
epen
dent
CD
11ch
igh
CD
8-/C
D11
b+
(‘mye
loid
’)
Mur
ine
plas
mac
ytoi
d D
Cs
!m
orph
olog
ical
sim
ilar t
o an
tibod
y pr
oduc
ing
plas
ma
cells
(B c
ells
)
!pr
oduc
tion
of h
igh
amou
nts
of In
terfe
ron
I (IF
N-α
,
IFN
-β) u
pon
viru
s in
fect
ion
!m
aint
enan
ce o
f per
iphe
ral t
oler
ance
!fu
rther
rece
ptor
s: P
DC
A-1,
Sig
lecH
, par
tly C
CR
9
!E2
-2 d
epen
dent
CD
11clo
w
PDC
A-1+
plas
mac
ytoi
d
CD
4+T
cells
CD
11b+
CD
8-
CD
8+T
cells
CD
11b-
CD
8+
BT
Sple
en
αDEC
205-
Ova
33D
1/αD
CIR
2-O
va
In v
ivo
antig
en ta
rget
ing
of D
C s
ubpo
pula
tions
indu
ces
diffe
rent
T c
ell r
espo
nses
in m
ice
Hei
dkam
p et
al.,
Sci
ence
Imm
unol
ogy,
in p
ress
Lehm
ann
et a
l., V
acci
nes,
201
6H
eidk
amp
et a
l., E
ncyc
l. of
Cel
l Bio
logy
, 201
6M
ilo e
t al.,
Blo
od, 2
013
Lind
mar
ket
al.,
J A
utoi
mm
, 201
3Lo
schk
o et
al.,
JI,
2011
-2Lo
schk
o et
al.,
JI,
2011
-1O
’Kam
phor
st e
t al.,
JI,
2010
Do
et a
l., E
JI, 2
010
Yam
azak
i and
Dud
ziak,
JI,
2008
Dud
ziak
et a
l., S
cien
ce, 2
007
Soar
es e
t al.,
JEM
, 200
7Sh
akha
ret a
l., N
at. I
mm
unol
. 200
5Li
ndqu
ist e
t al.,
Nat
. Im
mun
ol.,
2004
Than
kyo
ufo
ryou
ratte
ntio
n!