Download Dendritic cells

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
3 – 6%
Macrophages – extracellular pathogens (bacteria, yeast)
Dendritic cells – viruses, apoptotic cells
~1%
INNATE
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
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
Migration Pathways of PDC/IPC versus mDC into a
lymph node
mDC: afferent
lymphatics
IPC: HEV
Both migrate into the T-cell rich areas
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
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
ONE, TWO and DANGER signal hypothesis
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
DIFFERENTIATION AND MATURATION OF T CELLS IN
THE THYMUS
REGULATED T-CELL DIFFERENTIATION
preT-
CD4+CD8+
TCR
APC
Epithelial cell
immature T cell
pre T cell
pro T cell
SIGNALING RECEPTOR
NO ANTIGEN RECOGNIZING
RECEPTOR
ANTIGEN RECOGNIZING
RECEPTOR
T- CELL
DEVELOPMENT
Lymphoid precursor
NK cell
c-kit/CD44
RAG-1/RAG-2
Pro-T
-rearrangement
Pre-T
H rearrangement
Pre-T
-rearrangement

Surrogate L
Pre-B
L rearrangement
T
B
Selection
clonal deletion
Selection
clonal deletion
B
T
B
T
Mature-T
Pro-B
T
B
Mature-B
EVENTS OF T CELL DIFFERENTIATION IN THE THYMUS
1. Generation of NK cells
– no TCR
2. Differentiation of γδ and αβ
TCR carrying T cells
3. Selection of αβ TCR
– positive selection
– negative selection
4. Differentiation of CD4+ and
CD8+ T cell lineages
γδ T-cell
No selection
Pro-T
Early pre-T
Pre-Tαchain
Lck signal
IL-7-dependent
proliferation
β rearrangement
unsuccesful βchain
Late pre-T
CD4+CD8+
α rearrangement
αβ NKT-cell
CD4+CD8+
αβCD4+ αβCD8+
unsuccesful α-chain
no positive selection
negative selection
SELECTION OF T LYMPHOCYTES IN THE THYMUS
UNDER THE
CAPSULE
1. The primary T cell pool is
IL-7-dependent proliferation
biased to MHC-specificity (V
genes) 1-2% for one allotype
2. Focusing the T cell pool to
CORTEX
CD4-CD8DN
β+preTα
self MHC recognition (+)
3. Elimination of useless clones
4. Elimination of self agressive
TCRαβ
clones (-)
CD4+CD8+
5. CENTRAL TOLERANCE
TCR(-) sMHC+sP sMHC+fP fMHC+fP DP
6. Focusing The T cell repertoire
for recognition of non self
selection
7. Individualized T cell repertoire
+
+
CORTEX/
is available in the periphery


NO 
MEDULLA
– selection 8. CD4 and CD8 co-stimulatory
molecules are involved in
MEDULLA
positive selection
–
AICD – Activation
AICD
Induced Apoptosis
αβTCR
CD4+
αβTCR
CD8+
PERIPHERAL TOLERANCE
POSITIVE SELECTION OF DOUBLE POSITIVE (DP) T CELLS ALSO
DIRECTS CD4 AND CD8 SINGLE POSITIVE (SP)
T CELL COMMITMENT
CD4+CD8+
CD4+CD8+
Thymic
epithelial cell
MHC-I + peptide
complexes recruit CD8
MHC-II + peptide
complexes recruit CD4
POSITIVE SELECTION FOR 3 – 4 DAYS, SUCCESSIVE α-GENE
REARRANGEMENTS
BARE LYMPHOCYTE SYNDROME (BLS)
Lack of MHC class I – no CD8+ cells
Lack of MHC class II – no CD4+ cells
T-CELL DIFFERENTIATION IN THE PERIPHERY
CD8 TCR
CD8 TCR
CD8 TCR
CD4 TCR
CD4 TCR
APC
APC
CD4 TCR
APC
Ag
Ag
Ag
APC
APC
Memory T-cell
Activated T-cell
Mature naive T-cell
APC
SELECTION OF THE T CELL REPERTOIRE – CENTRAL TOLERANCE
POSITIVE SELECTION – Thymic education (no instruction for specificity)
Low avidity interaction of MHC - self peptide - TCR
Thymic epithelial cells
Self peptide composition and concentration (foreign peptides are not present)
Low peptide dose induces positive selection – special ligands
80-90% of DN (CD4-CD8-) T cells is NOT positively selected
PASSIVE CELL DEATH BY NEGLECTION
NEGATIVE SELECTION – Central self tolerance
High avidity of MHC - self peptide - TCR interaction
Ubiquitous and abundant self antigens are present in the thymus
High peptide dose induces negative selection
Any thymic antigen presenting cell: epithelial cells, bone marrow-derived
macrophages, dendritic cells
THE GENERATION OF SELF MHC + FOREIGN PEPTIDE SPECIFIC T
CELLS REQUIRES WEAK INTERACTION WITH SELF MHC + SELF PEPTIDE
SELF RESTRICTED AND TOLERANT PERIPHERAL T CELL REPERTOIRE
PHYSIOLOGICAL TRESHOLD
PERIPHERAL TOLERANCE
IMMUNE RESPONSES ARE NOT INITIATED IN THE PERIPHERY
Normal tissue cells do not express MHC class II
NO SIGNAL 1. for CD4+ Th activation
Normal tissue cells do not express co-stimulatory molecules
and do not produce T cell differentiating cytokines
NO SIGNAL 2. for CD4+ Th activation
Migration of naive T lymphocytes to normal tissues is limited
Antigen presenting cells are not activated in normal tissues
NO SIGNAL 3. for CD4+ Th activation
PERIPHERAL TISSUES TOLERIZE THEMSELVES
MECHANISMS OF PERIPHERAL TOLERANCE
ANERGY – Functional unresponsiveness, no IL-2 secretion
SIGNAL 1
SIGNAL 2
SIGNAL 3
Recognition of auto-antigen on tissue cell
No B7 and CD40 expression, no co-stimulation
Tissue resident professional APC are not activated
Innate immunity is not activated
No inflammation
CLONAL DELETION – Activation induced cell death
Requires persistant high antigen dose
Fas – FasL interaction
SUPPRESSION – Activity of other cells
Cytokine-mediated balance
Effector functions are inhibited by regulatory T cells
CLONAL IGNORANCE
No contact with the immune system
Immunologically privileged sites
Central nervous system, eye
No recognition in the periphery
HOMEOSTASIS OF POSITIVE AND NEGATIVE SELECTION IN
THE DEVELOPMENT OF THE AVAILABLE T LYMPHOCYTE
REPERTOIRE
Homozygote
Heterozygote
Ratio of negative selection increases with the
number of MHC genes
Ratio of positive selection
Number of MHC molecules