infectious diseases tissue transplantation elimination of tumors autoimmune diseases gatekeeper...
TRANSCRIPT
Infectious diseasesTissue transplantationElimination of tumorsAutoimmune diseases
Gatekeeper functionSensing pathogensPriming adaptive immune responsesMaintenance of self tolerance to self structures
THE ROLE OF PROFESSIONAL ANTIGEN PRESENTING CELLS IN THE IMMUNE RESPONSE
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
B cells – soluble proteins, toxins
ADAPTIVE – Ag specific
Macrophages – extracellular pathogens (bacteria, yeast)
Dendritic cells – viruses, apoptotic cells
INNATE3 – 6%
~1%
~25%
CHARACTERISTICS OF PROFESSIONAL ANTIGEN PRESENTING CELLS
Macrophage Dendritic cell B - lymphocyte
Ag uptake phagocytosis +++ phagocytosis +++ Ag-specific mIgvirus infection ++++ ++++
MHC expression induced +/+++ constitutive ++++ constitutive +++ bacteria, cytokine immature/mature +++/++++ activation ++++
Pesented Ag particulate Ag protein soluble protein intra/extracellular virus protein, allergen toxin pathogens apoptotic cell
Co-stimulation induced +/++ constitutive ++++ induced +/+++ éretlen/érett +++/++++
Localization lymphoid tissue lymphoid tissue lymphoid tissue connective tissue connective tissue peripheral blood body cavities epithelium
Lymph node evenly immature – tissue follicles mature – T cell area
Macrophage
Dendritic cell
Activated macrophage
Phagocytosis and degradation of backteria(LPS, TLR) DANGER SIGNAL
Activated dendritic cell
Virus, extracellular pathogens, inflammatory cytokines (LPS, TLR)DANGER SIGNAL
Monocyte
CHANGES OF TISSUE ENVIRONMENT INDUCES THE ACTIVATION OF MACROPHAGES AND DENDRITIC CELLS
LYMPHOID TISSUEBLOOD TISSUE
Tissue DC
Activated DC
DC AND T CELLS ENCOUNTER
T CELL ACTIVATION CIRCULATION
Naive T cells
Effector and memory T cells
TISSUE LYMPH NODE TISSUE
Lymphatics
InflammationPathogen
ACTIVATION AND MIGRATION OF DENDRITIC CELLS
ANTIGEN
Dendritic cells are sensors, gatekeepers and messengersActivation induces a phenotype essential for
the initiation of the adaptive immune response
INTERDIGITATING RETICULAR (MATURE DENDRITIC) CELL IN T CELL AREAS OF LYMPH NODES
NUCLEUS
CYTOPLASM
T CELL
T CELL
Cell-surface molecules of the immunoglobulin superfamily initiate lymphocyte adhesion to professional
antigen-presenting cells
Initial contactA.
Transient interactions are stabilized by Ag-bindingB.
A
Huang et al Immunity 2004
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 OT-II CD4+ T cells (5 µM SNARF, red).
Rapid DC Migration in the Subcapsular Space
Capture of an Ag-Specific T Cell by an Ag-Bearing DC
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
Activated dendritic cells act as professional antigen presenting cells
MHC-peptide complexes 1. signal STRANGERCo-stimulatory molecule 2. signal AMPLIFICATIONCytokines 3. signal DANGER
They are in close contact with
specific T lymphocytes
CONTACT OF DENDRITIC CELLS AND T - LYMPHOCYTES
IN LYMPHOID ORGANS
Morphology of plasmacytoid dendritic cells IPC/DC2
monocytepDC
Scanning EM Transmission EM
Plasmacytoid DCs control the function of many immunocytes
Role in immune response and in the pathogenesis of autoimmune diseases and cancer
HIV infects PDC IFNα is impotant inSLE pathology
TRIF
TANK
IKKε TBK1
IRF-3
TRIF
TRAM
TLR3
TLR4
MyD88
IRF-5
TLR7TLR8TLR9
IFN-βIFN-α1
RIG-1
Ig production by B cells is induced
Type I interferon receptor
IRF-7
Enhanced NK cell cytotoxic activity
Activation of and γδ T cells
Cross-presentation by conventional dendritic cells is enhanced
IRAK-1
TRAF-6
IRF-7
PLASMACYTOID DENDRITIC CELLS AS PROFESSIONAL TYPE I INTERFERON SECRETING CELLS
Vírus infection
Migration Pathways of PDC/IPC versus mDC into a lymph node
IPC: HEV
mDC: afferent lymphatics
Both migrate into the T-cell rich areas
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