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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