Infectious diseases Tissue transplantation Elimination of tumors Autoimmune diseases Gatekeeper function Sensing pathogens Priming adaptive immune responses Maintenance 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 INNATE 3 – 6% ~1% ~25%

CHARACTERISTICS OF PROFESSIONAL ANTIGEN PRESENTING CELLS Macrophage Dendritic cellB - 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

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 TISSUEBLOODTISSUE

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 Inflammation Pathogen ACTIVATION AND MIGRATION OF DENDRITIC CELLS ANTIGEN

Dendritic cells are sensors, gatekeepers and messengers Activation 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

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 37 o C, 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 complexes1. signal STRANGER Co-stimulatory molecule 2. signal AMPLIFICATION Cytokines3. 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 EMTransmission 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 in SLE pathology

TRIF TANK IKKεTBK1 IRF-3 TRIF TRAM TLR3 TLR4 MyD88 IRF-5 TLR7 TLR8 TLR9 IFN-β IFN-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