Fertőző betegségekSzervátültetésTumorok eliminálása

Gatekeeper funkcióKórokozók „érzékelése”Adaptív immunválasz elindításaSaját struktúrákkal szembeni tolerancia fenntartása

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

INNATE

3 – 6%

~1%

~25%

CHARACTERISTICS OF PROFESSIONAL ANTIGEN PRESENTING CELLS

Macrophage Dendritic cell B - lymphocyte

Ag uptake phagocytosis +++ phagocytosis +++ Ag-specific mIg virus 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

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

MYELOID LYMPHOID

BONE MARROW

CMP CLP

DC2/plasmacytoid

IPC/preDC2

Pre-TαVλ5

CD34+CLA+

CD11c+CD1a+

Langerhans/LC

CD34+CLA-

CD11c+CD1a-

Interstitial

BLOOD

TISSUE

Macrophage

CD14+

Monocyte/preDC1

DC1/myeloid

CD34+ HPC

ORIGIN AND DIFFERENTIATION OF HUMAN DENDRITIC CELLS

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 induce a phenotype essential for 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

IDCTISSUE

ACTIVATION

Antigen uptake

Activation

Mobility

Antigen processing & presentation

MHCI/MHCII

MHC II

PS-R

MR

Fc RIIg

a bV 5

a bV 3

NaíveT cell

B7

ICAM-1

CD40

SLAMCCR7

MDR

MDC DC1/DC2 LYMPHOID ORGANS

DC – T interactionCognate Th/Tc activation

Th1/Th2 instruction

HUMAN MYELOID DENDRITIC CELLS

CD14

DC-SIGNM HC I M HC II

CD36PS-R

M R

HSP+peptide

Fc RIIg

a bV 5

a bV 3

HIV-1

N aíveT ce ll

CD46M easles

CD1aGlycolipid

Protein

Peptides

Toll

Toll

M HC II

C 91D

CRABCA1

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

ONE, TWO and DANGER signal hypothesis

Matzinger, P. Science, 296. 301- (2002)

Self- nonself models

The danger hypothesis & co-stimulation

Fuchs & Matzinger 1995

Full expression of T cell function and self tolerance depends upon when and where co-stimulatory molecules are expressed.

Apoptotic cell death.A natural, often usefulcell death.

APC

APC

No danger

No dangerCell containing onlyself antigens

Innocuous challenge to the immune system fails to activate APC and failsto activate the immune system

The danger hypothesis

APC

APC

Necrotic cell deathe.g. tissue damage,virus infection etc

Pathogens recognisedby microbial patterns

DANGER

APC that detect ‘danger’ signals express costimulatorymolecules, activate T cells and the immune response

• 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.

Some implications of the danger hypothesis

Doesn’t exclude self-nonself discrimination, but is very hard to enequivocally disprove experimentally

LOCALIZATION ANTIGEN UPTAKE

MHCLOCALIZATION

ANTIGEN PRESENTATION

ANTIGEN/PATHOGEN

B-cell Lymphoid tissue,Peripheral blood

BCR-mediated endocytosis,pinocytosis

MCII/CIIVCell surface (activation)

low antigen doseco-stimulation

toxins, víruses, bacteria,

any protein

Macrophage Lymphoid tissue, connective tissue,

body cavities

phagocytosisFcR, CR

MCIICell surface (activation)

high antigen doseco-stimulation

intracellular bacteria,

other pathogensparticles

Immature DC

Epithelium,skin,

tissues

phagocytosis,macropinocytosi

s, pinocytosis

intracellularMCII

none víruses, allergens,

bacteria, lipids, any protein

Maturing DC

afferent lymph Not significant intracellularCIIV

inefficient

Mature DC Lymph nodeT-cell areas

none Cell surface very efficientco-stimulation

PROFESSIONAL ANTIGEN PRESENTING CELLS