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