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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)
80-90% of DN (CD4-CD8-) T cells is NOT positively selected
PASSIVE CELL DEATH BY NEGLECT
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
NOT COMPLETE
γδ T-cells
•MHC-independent, CD1c and CD1d dependent
•Double megative
•comprise up to 50% of the intra-epithelial lymphocyte population
•Expanded in intracellular bacterial infections(Mycobacterium
tuberculosis and Listeriamonocytogenes), extracellular infections
(Borreliaburgdorferi)
•a population that is expanded in certain disease states such as
celiac disease
Pierre Vantourout and Adrian Hayday 88 | FEBRUARY 2013 | VOLUME 13
THE ROLE OF PROFESSIONAL ANTIGEN
PRESENTING CELLS IN THE IMMUNE RESPONSE
Gatekeeper function
Sensing pathogens
Priming adaptive immune responses
Maintenance of self tolerance to self structures
Infectious diseases
Tissue transplantation
Elimination of tumors
Autoimmune diseases
Dendritic cells are sensors, gatekeepers and messengers
Activation induces a phenotype essential for
the initiation of the adaptive immune response
MHC class II molecules stained green
lysosomal protein stained red
CONTACT OF DENDRITIC CELLS AND T
- LYMPHOCYTES
IN LYMPHOID ORGANS
Activated dendritic cells act as professional antigen
presenting cells
MHC-peptide complexes
Co-stimulatory molecule
Cytokines
1. signal STRANGER
2. signal AMPLIFICATION
3. signal DANGER
They are in close contact with
specific T lymphocytes
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.
A.
A
Transient interactions are stabilized by Ag-binding
Initial contact
DC-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN).
CHANGES OF TISSUE ENVIRONMENT INDUCES THE ACTIVATION OF
MACROPHAGES AND DENDRITIC CELLS
Phagocytosis and degradation of backteria
(LPS, TLR) DANGER SIGNAL
Macrophage
Monocyte
Activated macrophage
Dendritic cell
Activated dendritic cell
Virus, extracellular pathogens, inflammatory cytokines (LPS, TLR)
DANGER SIGNAL
BLOOD
TISSUE
LYMPHOI
D 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
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. coinjection of OT-I CD8+ T cells (5 µM CFSE, green) and
OT-II CD4+ T cells (5 µM SNARF, red).
Huang et al Immunity 2004
Morphology of plasmacytoid dendritic cells
IPC/DC2
pDC
monocyte
In human TLR9 is only expressed in
pDCs
Scanning EM
Transmission EM
DC-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN).
Migration Pathways of PDC/IPC versus mDC into a
lymph node
mDC: afferent
lymphatics
IPC: HEV
Both migrate into the T-cell rich areas
PDC efficiently crosspresent exogenous antigens to CD8+ T-cells
PLASMACYTOID DENDRITIC CELLS AS PROFESSIONAL TYPE I INTERFERON SECRETING
CELLS
TLR4
TRAM
TRIF
Vírus infection
Enhanced NK cell cytotoxic activity
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
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