Transcript Dendritic cells

THE ROLE OF PROFESSIONAL ANTIGEN
PRESENTING CELLS IN THE IMMUNE
RESPONSE
Gatekeeper funkció
Kórokozók „érzékelése”
Adaptív immunválasz elindítása
Saját struktúrákkal szembeni
tolerancia fenntartása
Fertőző betegségek
Szervátültetés
Tumorok eliminálása
PROFESSIONAL ANTIGEN PRESENTING
CELLS
Express MHC class I and class II molecules
Express co-stimulatory molecules (B7, CD40)
Take up extracellular antigens
B cells – soluble proteins, toxins (ADAPTIVE)
Macrophages
– extracellular pathogens (bacteria, yeast)
INNATE
– particles
Dendritic cells – viruses, apoptotic cells
PROFESSIONAL ANTIGEN PRESENTING CELLS
Express MHC class I and class II molecules
Express co-stimulatory molecules (CD40, B7)
Take up extracellular antigens
~25%
B cells – soluble proteins, toxins
ADAPTIVE – Ag specific
Macrophages – extracellular pathogens (bacteria, yeast)
3 – 6%
Dendritic cells – viruses, apoptotic cells
INNATE
~1%
CHARACTERISTICS OF PROFESSIONAL ANTIGEN PRESENTING CELLS
Macrophage
Ag uptake
phagocytosis +++
Dendritic cell
phagocytosis +++
virus infection ++++
B - lymphocyte
Ag-specific mIg
++++
MHC expression induced +/+++
bacteria, cytokine
constitutive ++++
constitutive +++
immature/mature +++/++++ activation ++++
Pesented Ag
particulate Ag
intra/extracellular
pathogens
protein
virus protein, allergen
apoptotic cell
soluble protein
toxin
Co-stimulation
induced +/++
constitutive ++++
éretlen/érett +++/++++
induced +/+++
Localization
lymphoid tissue
connective tissue
body cavities
evenly
lymphoid tissue
connective tissue
epithelium
immature – tissue
mature – T cell area
Lymph node
lymphoid tissue
peripheral blood
follicles
CO-STIMULATION IS ESSENTIAL FOR PRIMING OF
NAIVE T LYMPHOCYTES
The antigen-specific and the co-stimulatory signal
has to be induced in concert to induce T
lymphocyte activation
The antigen-specific and co-stimulatory signals
can be delivered simultaneously by professional
antigen presenting cells, only
The antigen-specific and the co-stimulatory
singnals has to be delivered by the same
professional antigen presenting cell
ORIGIN AND DIFFERENTIATION OF HUMAN DENDRITIC
CELLS
CD34+ HPC
BONE MARROW
MYELOID
LYMPHOID
CMP
CLP
CD34+
CLA+
CD34+
CLA-
CD11c+
CD1a+
CD11c+
CD1a-
BLOOD
CD14+
Monocyte/preDC1
Langerhans/LC
Interstitial
DC1/myeloid
Macrophage
TISSUE
Pre-Tα
Vλ5
IPC/preDC2
DC2/plasmacytoid
CHANGES OF TISSUE ENVIRONMENT INDUCES THE
ACTIVATION OF MACROPHAGES AND DENDRITIC
CELLS
Phagocytosis and degradation of backteria
(LPS, TLR) DANGER SIGNAL
Macrophage
Monocyte
Dendritic cell
Activated macrophage
Activated dendritic cell
Virus, extracellular pathogens, inflammatory cytokines (LPS, TLR)
DANGER SIGNAL
BLOOD
TISSUE
LYMPHOID TISSUE
ACTIVATION AND MIGRATION OF DENDRITIC CELLS
TISSUE
LYMPH NODE
Lymphatics
Activated DC
TISSUE
Effector and memory T
cells
Inflammation
Pathogen
Naive T cells
ANTIGEN
Tissue DC
DC AND T CELLS
ENCOUNTER
T CELL ACTIVATION
CIRCULATION
Dendritic cells are sensors gatekeepers and messengers
Activation induce a phenotype essential for
initiation of the adaptive immune response
INTERDIGITATING RETICULAR (MATURE DENDRITIC) CELL
IN T CELL AREAS OF LYMPH NODES
NUCLEUS
T CELL
T CELL
CYTOPLASM
Cell-surface molecules of the immunoglobulin superfamily
initiate lymphocyte adhesion to professional
antigen-presenting cells.
B. Transient interactions are stabilized by Ag-binding
A.
A
Initial contact
Rapid DC Migration in the Subcapsular
Space
Bone-marrow derived DCs (either 5 µM
CFSE, green) or (50 µM Cell Tracker Blue,
blue) were injected into the footpad of a
C57BL/6 mouse, followed 18 hours later
by intravenous injection of freshly
isolated polyclonal CD4+ T cells (5 µM
SNARF, red) and CD8+ T cells (5 µM CFSE
and 5 µM SNARF, yellow). The draining LN
was removed 6 hours after injection
Capture of an Ag-Specific T Cell by an
Ag-Bearing DC
Bone-marrow derived DCs (yellow) were
pulsed with 1 µM Ova 4 peptide and 10 µM
Ova for 1 hour at 37oC, then injected into the
footpad of a C57BL/6 recipient. This was
followed 6 hours later by i.v. co-injection of
OT-I CD8+ T cells (5 µM CFSE, green) and OTII CD4+ T cells (5 µM SNARF, red).
Huang et al Immunity 2004
CONTACT OF DENDRITIC CELLS
AND T - LYMPHOCYTES
IN LYMPHOID ORGANS
Activated dendritic cells act as professional
antigen presenting cells
MHC-peptide complexes 1. signal STRANGER
Co-stimulatory molecule 2. signal AMPLIFICATION
Cytokines
3. signal DANGER
They are in close contact with
specific T lymphocytes
HUMAN MYELOID DENDRITIC CELLS
Peptides
MHC II
G
N
Naíve
T cell
FcgRII
Naíve
T cell
Exo
som
es
MR
CD46
B7
Measles
MR
CD91
HSP+peptide
CD14 Toll
aVb5
Toll
ABCA1
HIV-1
DC-SIGN
I
-S
I
MHC II
MHC II
DC
Protein En
zym MHC I
es
MH
C
aVb3 PS-R
CD36
IDC
TISSUE
Antigen uptake
Activation
CR
aVb3
aVb5
ICAM-1
CD1a
Glycolipid
FcgRII
PS-R
CD40
MDR
ACTIVATION
Mobility
Antigen processing & presentation
MHCI/MHCII
CCR7
SLAM
MDC  DC1/DC2
LYMPHOID ORGANS
DC – T interaction
Cognate Th/Tc activation
Th1/Th2 instruction
Morphology of plasmacytoid dendritic cells
IPC/DC2
pDC
Scanning EM
monocyte
Transmission EM
Plasmacytoid DCs control the function of many
immunocytes
HIV infects PDC
IFNα is impotant in
SLE pathology
Role in immune response and in the pathogenesis of autoimmune
diseases and cancer
PLASMACYTOID DENDRITIC CELLS AS PROFESSIONAL TYPE I
INTERFERON SECRETING CELLS
Enhanced NK cell cytotoxic activity
TLR4
TRAM
TRIF
Vírus infection
TLR7
TLR8
TLR9
TLR3
TRIF
MyD88
IRAK-1
TRAF-6
TANK
Activation of  and γδ T cells
RIG-1
IKKε
TBK1
IRF-3
IRF-5
IRF-7
IFN-β
IFN-α1
Cross-presentation by conventional
dendritic cells is enhanced
IRF-7
Type I interferon receptor
Ig production by B cells is
induced
Migration Pathways of PDC/IPC versus mDC into a
lymph node
mDC: afferent
lymphatics
IPC: HEV
Both migrate into the T-cell rich areas
ONE, TWO and DANGER signal hypothesis
Self- nonself models
Matzinger, P. Science, 296. 301- (2002)
The danger hypothesis & co-stimulation
Full expression of T cell function and self tolerance
depends upon when and where co-stimulatory molecules are expressed.
Cell containing only
self antigens
No danger
Apoptotic cell death.
A natural, often useful
cell death.
No danger
APC
APC
Innocuous challenge to the immune system fails to activate APC and fails
to activate the immune system
Fuchs & Matzinger 1995
The danger hypothesis
Necrotic cell death
e.g. tissue damage,
virus infection etc
APC
DANGER
Pathogens recognised
by microbial patterns
APC
APC that detect ‘danger’ signals express costimulatory
molecules, activate T cells and the immune response
Some implications of the danger hypothesis
• There is no window for tolerance induction in neonates
• Neonatal T cells are not intrinsically tolerant but the neonatal environment
predisposes to tolerance
• Antigens induce tolerance or immunity depending upon the ability of the
immune system to sense them as ‘dangererous’, and not by sensing whether
they are self or ‘non-self’.
• Apoptosis, the ‘non-dangerous’ death of self cells may prevent autoimmunity
when old or surplus cells are disposed of.
• Suggests that tolerance is the default pathway of the immune system on
encountering antigens.
• Explains why immunisations require adjuvants to stimulate cues of danger
such as cytokines or costimulatory molecule expression.
Doesn’t exclude self-nonself discrimination, but is very hard to
enequivocally disprove experimentally
PROFESSIONAL ANTIGEN PRESENTING CELLS
LOCALIZATION
ANTIGEN
UPTAKE
MHC
LOCALIZATION
ANTIGEN
PRESENTATION
ANTIGEN/
PATHOGEN
B-cell
Lymphoid tissue,
Peripheral blood
BCR-mediated
endocytosis,
pinocytosis
MCII/CIIV
Cell surface
(activation)
low antigen dose
co-stimulation
toxins, víruses,
bacteria,
any protein
Macrophage
Lymphoid tissue,
connective tissue,
body cavities
phagocytosis
FcgR, CR
MCII
Cell surface
(activation)
high antigen dose
co-stimulation
intracellular
bacteria,
other pathogens
particles
Immature
DC
Epithelium,
skin,
tissues
phagocytosis,
macropinocytosi
s, pinocytosis
intracellular
MCII
none
víruses, allergens,
bacteria, lipids,
any protein
Maturing
DC
afferent lymph
Not significant
intracellular
CIIV
inefficient
Mature DC
Lymph node
T-cell areas
none
Cell surface
very efficient
co-stimulation