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BIOL 1010U

IMMUNOLOGY ANTIGEN PRESENTING CELLS -APC express MHC II and costimulatory molecules to present exogenous antigens to lymphocytes -Dendritic Cells = most efficient APC at initiating primary immune response and inducing self tolerance Barriers: Low [antigen], small pop of T cells, spatial consideration, TCR with low affinity DENDRITIC CELLS Problems with DCs: Infrequent, Different varieties, Difficult to purify and obtain in large numbers Distinct phenotypes at different stages in life cycle State of differentiation altered in culture Introduction -Antigen capture and processing is in peripheral tissues. -Initiation of 1° immune response localized in lymph node and spleen -Activated T cells egress lymph nodes, recirculate through tissue and direct effector response -Dendritic Cells- APC that initiate innate and adaptive (T mediated) immune response -occupy discrete regions in lymphoid and nonlymphoid tissue -phenotypic changes facilitate antigen capture in the periphery and movt to T cell regions of lymph nodes to present on MHC II DC Structure and Life-Cycle -numerous surface veils, paucity of lysosomes, distinct multivesicular vacuoles -100 x more efficient at initiation 1° immune response then macrophages -Differentiation pathway widely distributed in lymphoid and non-lymphoid organs. 2 major DC pathways 1. Myeloid Pathway- includes Langerhans Cells (LCs) and Interstitial DCs (int DCs) -LC has Birbeck granule (like endosomes generated by expression of Lectin molecule) - LC found in epithelial intDCs found in all other tissues -both secrete IL-12 intDCs make IL-10 (induce naïve B cell Differentiation) 2. Lymphoid Pathway- includes plasmacytoid DCs (pDCs) - secrete large amounts of type I interferons (modulate T cell differentiation) MYELOID DC LINEAGE 1.DC progenitors originate from the bone marrow and enter blood to go to peripheral non-lymphoid sites 2. Immature (processing) DCs differentiated for optimal antigen uptake and processing. -MHC production, formation of foreign peptide-MHC complexes 3. Inflammatory mediators promote maturation-DCs migrate as “veiled” cells in afferent lymph to 2°lymph tissues 4. Mature (presenting) DCs-in T cell areas of lymph nodes/spleen -have optimal co-stimulatory activity (surface molecule expression and cytokine secret) (Raymond removed an image of antigen capture by DCs followed by migration to lymph nodes and presentation to T cells.) -DCs from non-inflamed environment play a major role in generating tolerace to peripheral antigens -Migration to lymph nodes after capturing endogenous material provide signal 1 onlytolerance The DENDRITIC CELL SYSTEM-DISTRIBUTION AND PHENOTYPES Just know that multiple phenotypes at different parts of life Nonlymphoid organs Langerhans cells, interstitial dendritic cells Circulation Afferent lymph veiled cells, blood dendritic cells Lymphoid organs Lymphoid dendritic cells, interdigitating cells INTERNALIZATION 1. Phagocytosis 2. Pinocytosis 3. Macropinocytosis 4. Receptor Mediated Endocytosis -high capacity -high affinity FUNCTIONF OF DC Properties of Immature DC 1. Highly enriched MHC class II (remain intracellular) 2. Samples vast volumes of bathing fluid (Macropinocytosis) –low affinity, high capacity MACROPHAGES- most things degraded in lysosomes DENDRITIC CEL- most reexpressed on MHCII surface -when inside DC TLR recognize PAMP to activate DCs 1. Capturing and Processing Antigens in non lymphoid Tissue (IMMATURE DCS) -capacity to interiorize and process whole protein antigens varies with the state of maturation of DCs Langerhan Cells- efficiently present protein antigens (activity lost within 12 hours of isolation) -as cells lose presentation of whole protein Ag, they develop strong binding and stimulatory activity for T cells Upregulate –ICAM-1/ICAM-2/LFA-1/DC-SIGN/B7.1/B7.2 - secrete DC-CK- chemokine that attracts naïve T cells (1) Antigen capture at early point in life history (2) Antigen presentation (adhesion, costimulatory molecules) later in life history relocation to lymph nodes Highly Regulate Maturation Process -influenced by GM-CSF, IL-4, TNFα, IL-1, CD40L 1. Alteration of antigen-capture and processing phenotype of DCs 2. Expression of co-stimulatory activities Features of Antigen Capture and Processing by “immature” DCs 1. Synthesis of intracellular MHCII expressd in unique endosomal compartment (MIIV) 2. Freshly isolated DCs rapidly internalize solute through macropinocytosis (see above) 3. Macropinocytosis ON: GM-CSF, IL
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