Antigen Presentation and Dendritic Cells .


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5/16/06. J. R. Lingappa, Pabio 552. 2. Antigen Presentation and Dendritic Cells. A. How T cells are prepared to perceive microbial antigens: MHC I versus MHC II presentationIntracellular antigens (normally popular) displayed through MHC I on antigen exhibiting cells (APC) to CD8 (cytotoxic) T cells. Note: MHC class I communicated on all phone types.Intravesicular antigens (ordinarily bacterial or parasitic) p
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Antigen Presentation and Dendritic Cells Outline: 1. Survey of MHC Class I and MHC Class II Presentation 2. Outline of Dendritic Cells Dendritic Cell Paradoxes Cross Presentation Problems in Cross Presentation Pathogens Exploit DCs as an Entry Route for Infection Pathogens Block Antigen Presentation Additional Reading J. R. Lingappa, Pabio 552

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1. Audit of MHC Class I and MHC Class II Presentation: Antigen Presentation and Dendritic Cells A. How T cells are prepared to perceive microbial antigens : MHC I versus MHC II presentation Intracellular antigens (ordinarily popular) exhibited through MHC I on antigen displaying cells (APC) to CD8+ (cytotoxic) T cells. Note: MHC class I communicated on all cell sorts. Intravesicular antigens (normally bacterial or parasitic) introduced through MHC II on APC to CD4+ T cells From Janeway, Immunobiology, fifth version J. R. Lingappa, Pabio 552

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Antigen Presentation and Dendritic Cells Viral antigens from cytosol are displayed by MHC class I 1. Audit of MHC Class I and MHC Class II Presentation, cont.: A. MHC class I presentation: From Janeway, Immunobiology, fifth release J. R. Lingappa, Pabio 552

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Antigen Presentation and Dendritic Cells MHC class I chains are held in the ER until peptide ties 1. Audit of MHC Class I and MHC Class II Presentation, cont.: A. MHC class I presentation, cont.: From Janeway, Immunobiology, fifth version J. R. Lingappa, Pabio 552

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Antigen Presentation and Dendritic Cells Review of MHC Class I and MHC Class II Presentation, cont.: B. MHC class I presentation brings about authoritative of T cell receptor and actuation of CD8+ (cytotoxic) T cells: From Janeway, Immunobiology, fifth release J. R. Lingappa, Pabio 552

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Antigen Presentation and Dendritic Cells Endocytosed bacterial antigens introduced by MHC class II 1. Audit of MHC Class I and MHC Class II Presentation, cont.: C. MHC class II presentation: From Janeway, Immunobiology, fifth release J. R. Lingappa, Pabio 552

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Antigen Presentation and Dendritic Cells Invariant chain anticipates different proteins in the ER from official to MHC class II Review of MHC Class I and MHC Class II Presentation, cont.: C. MHC class II presentation, cont.: From Janeway, Immunobiology, fifth version J. R. Lingappa, Pabio 552

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Antigen Presentation and Dendritic Cells Review of MHC Class I and MHC Class II Presentation, cont.: D. MHC Class II presentation on APC\'s enacts CD4+ T cells: From Janeway, Immunobiology, fifth release J. R. Lingappa, Pabio 552

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Antigen Presentation and Dendritic Cells 1. Survey of MHC Class I and MHC Class II Presentation, cont.: E. Actuation of credulous T cells requires two signs ("co-incitement"). 1. Flag 1: acknowledgment of peptide-MHC buildings by T cell receptor. 2. Flag 2: connections between B7(CD80 or CD86) on the APC cell surface and CD28 receptors on the T cell. B7:CD28 restricting is advanced and maintained by CD40 authoritative to CD40 ligand. Just PROFESSIONAL APCS CAN CO-STIMULATE AND ACTIVATE NAÏVE T CELLS. Proficient APCS ONLY EXPRESS B7 WHEN ACTIVATED BY INFLAMMATION. J. R. Lingappa, Pabio 552

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Antigen Presentation and Dendritic Cells 3. Diagram of Dendritic Cells: Basic Concepts: 1. DCs are the best proficient APCs - Only expert APCs are able initiation of gullible T cells -Amateur APCs do not have the capacity to inspire flag 2 and in this way just perceive previously enacted T cells. Most cells that get to be distinctly contaminated are novice APCs. - DCs: best due to costimulation effectiveness, wide dissemination, area at basic sentinel destinations, and capacity to relocate -Activated T cells thusly enact B cells, T cells, and macrophages -Thus, DCs start insusceptible reactions that are directed by other cell sorts. J. R. Lingappa, Pabio 552 From Janeway, Immunobiology, sixth version

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Antigen Presentation and Dendritic Cells 2. Outline of Dendritic Cells, cont.: A. Essential Concepts, cont.: 2. DCs exist in 2 practically extraordinary states (develop and youthful). DCs were at first thought to be great phagocytes and feeble APCs. Change in our comprehension of DC: perception that naturally secluded Langerhans cells were at first frail APCs, yet after culture for 1-3 days in nearness of antigen they get to be distinctly fit for presentation (because of development). Juvenile and develop DC\'s capacity in an unexpected way. 3. DCs interface the inborn and adapative safe reaction. As juvenile cells, they go about as sensors of nature. Upon incitement, dendritic cells experience development and movement to optional lymphoid organs where they fortify guileless T cells that then go ahead to enact T cells, B cells, and macrophages. DC\'s are the connection between the inborn and versatile invulnerable reaction. J. R. Lingappa, Pabio 552

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2. Diagram of Dendritic Cells, cont.: B. Juvenile Dendritic Cells: Sentinels Antigen Presentation and Dendritic Cells Specialize in endocytosis (antigen take-up) including reusing of MHC I&II Express low levels of MHC class I and MHC class II particles on cell surface Short half existence of MHC class II on surface Rich in vesicles with lysosomal markers that are loaded with MHC II and HLA-DM called MHC class II compartments or MIIC Express low levels of co-stimulatory atoms on cell surface Antigens taken up are held for use as immunogenic peptides days after the fact g. Fringe area: blood, lymphoid, & non-lymphoid tissues (skin &mucosa) From Mellman and Steinman, Cell 106: 255 (2001) J. R. Lingappa, Pabio 552

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Antigen Presentation and Dendritic Cells 2. Diagram of Dendritic Cells, cont.: C. The Process of Dendritic Cell Maturation: Step 1: DCs sense pathogens or fiery signs. i. Microbial items ii. Genius fiery cytokines Maturation happens endless supply of microbial items or cytokines. Joins effective antigen presentation to a peril flag: favors initiation of T cells ONLY in nearness of a pathogen. Step 2: youthful DC\'s catch the organism that has been detected through: i. Phagocytosis (for particulate antigens) ii. Receptor-interceded endocytosis iii. Macropinocytosis (for dissolvable antigens) Step 3: Migration of DC\'s from site of disease towards T cell regions of the proximal LN by means of afferent lymphatics. Upregulation of the chemokine receptor CCR7 on DC which drives DC relocation to: 1. lymphatic vessels by restricting 6Ckine discharged by lymphatic endothelial cells 2. depleting lymph hubs (DNL) by restricting MIP 3  J. R. Lingappa, Pabio 552

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Antigen Presentation and Dendritic Cells 2. Diagram of Dendritic Cells, cont.: C. The Process of Dendritic Cell Maturation: Step 4: Decreased endocytic & phagocytic capacity Due to down-direction of macropinocytosis & phagocytosis Mechanism: diminished enactment of Cdc42 & Rac (GTPases that manage actin). Clathrin-interceded endocytosis proceeds with Step 5: Increased surface articulation of MHCII bound to peptide Little or no expansion in mRNA and protein combination Almost altogether because of post-translational occasions, particularly intracellular transport In juvenile DCs, MHC II gathers in late endosomes and lysosomes In develop DCs, MHC II aggregates at cell surface Step 6: Enhanced articulation of co-stimulatory atoms B7 (CD80 and CD86, CD40) and Fas Step 7: Release of cytokines and chemokines by DCs Including IL-12, IL-18, IL-10 Cytokines energize T cell reactions (see Responses to DCs, underneath) J. R. Lingappa, Pabio 552

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Antigen Presentation and Dendritic Cells 2. Review of Dendritic Cells, cont.: D. Develop DC\'s: Antigen Presenting Cells a. Diminished limit with regards to antigen take-up b. Expanded antigen presentation and T cell incitement (superior to macrophages) c. Redistribution of MHC II from intracellular compartments to cell surface d. MIICs supplanted by CIIVs where peptide stacking happens e. CIIVs convey peptide-stacked MHC II to cell surface f. Emotional increment in cell surface articulation of co-stimulatory particles g. MHC II stacked with peptide at cell surface has an any longer half life h. Surface articulation of co-stimulatory atoms i. Long dendritic procedures (film folds) for catch of T cells j. Chemokine receptor expression for movement & homing to lymph hubs From Mellman and Steinman, Cell 106: 255 (2001) MIIC J. R. Lingappa, Pabio 552

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Antigen Presentation and Dendritic Cells 3. Dendritic Cell Paradoxes: 1. How are 9 - 16 amino corrosive peptides (perfect for antigen presentation) created? Lysosomes ordinarily corrupt proteins to single amino acids. DC\'s control lysosomal proteolysis in a formatively connected manner. This may occur in endosome-like vesicles that are particular for antigen preparing. Macrophages contain large amounts of proteases bringing about quick and finish degradation. Conversely, DC\'s are protease poor with constrained limit with respect to proteasomal degradation. Dellamare et al., Science 307: 1630, 2005 Limited lysosomal proteolysis favors antigen presentation. J. R. Lingappa, Pabio 552

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Antigen Presentation and Dendritic Cells 3. Dendritic Cell Paradoxes: 2. How do DC\'s available antigen that was sequestered in lysosomes for quite a long time? Lysosomal catalyst substance, pH, and morphology are directed in DC\'s. A. Control of post-translational trafficking of MHC II: 1. Direction of cathepsin S Cathepsin S separates Ii chain that possesses the MHC II peptide restricting notch. Youthful DCs: cystatin C antiprotease moderates Ii cleavage - MHC II goes to lysosomes. Develop DC\'s: cystatin C movement diminishes, cathepsin S action increments and more MHC II achieves the cell surface. 2. Control of vacuolar ATPase Low pH favors peptide stacking onto MHC II DC development brings down endosomal pH Low pH result

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