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Ag presentation & role of mhc somu

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Antigen processing and presentation and role of major histocompatibility complex molecules- Dr Somshekhar Hogtapur, PhD Scholor, Dept Of Microbiology, Vety college Bangaluru, India

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Ag presentation & role of mhc somu

  1. 1. Innate Immunity Is that enough? ……………..not enough
  2. 2. Triggering Acquired Immunity Innate Immune Defenses: Invaders with low virulence are rapidly eliminated Inflammation-not foolproof & uncomfortable and damagingTo DEFEND EFFECTIVELY …… Acquired Immune System
  3. 3. Antigen Presentation & Role of Major Histocompatibility ComplexCourse-VPP 703Course Teacher-Dr Suguna Rao ProfPresentation By-Dr Somshekhar
  4. 4. Triggering Acquired Immunity…. Foreign Material-captured, processed, and presentedAntigen Processing & Presenting Cells- ◦ Dendritic cells ◦ Macrophages  B cells (Minor role in Primary Response)
  5. 5. Antigen ProcessinggAttracted by alarmins(damagedcells)
  6. 6. T cells do not recognise native antigens B B B B B BB B B Y Y Y Y Y YYY Y Y Y Y Y Y YCross-linking of surface Proliferation and antibodymembrane Ig production T T No proliferation No cytokine release Y Y
  7. 7. Antigens must be processed in order to be recognised by T cells T Y Cell surface peptides of Ag presented by cells that express MHC antigens Soluble Soluble native Ag peptides of Ag Cell surface Cell surface native Ag peptides of Ag ANTIGEN PROCESSINGNo T cell No T cell No T cell No T cell T cellresponse response response response response
  8. 8. The site of pathogen replication or mechanism of antigenuptake determines the antigen processing pathway used EXTRACELLULAR OR ENDOSOMAL REPLICATION Vesicular Compartment Y Contiguous with extracellular fluid Exogenous processing (Streptococcal, Mycobacterial antigens) INTRACELLULAR REPLICATION Cytosolic compartment Endogenous processing (Viral antigens) Distinct mechanisms of antigen generation are used to raise T cells suited to the elimination of endogenous or exogenous pathogens
  9. 9. Antigens generated by endogenous and exogenousantigen processing activate different effector functions EXOGENOUS PATHOGENS Y ENDOGENOUS PATHOGENSEliminated by: Eliminated by:Antibodies and phagocyte Killing of infected cells by CTL thatactivation by T helper cells that use antigens generated byuse antigens generated by ENDOGENOUS PROCESSINGEXOGENOUS PROCESSING
  10. 10. What is MHC??????(Gorer & GeorgeSnell) Every mammalian speciespocesses a tightly linked clusterof genes-Major HistocompabilityComplex (MHC), whose productsplay role in intracellularrecognition and in discriminationbetween self and nonself. T cells recognize antigenonly when it is combined with anself MHC molecule (MHC
  11. 11.  Most cells can present antigen with class I MHC molecules to CD8+ Tc cells-Target cells Cells that display peptides associated with class II MHC molecules to CD4+ TH cells-Antigen presenting cells (APCs)
  12. 12. Structures of MHC Class I & II
  13. 13. Antigen Processing Exogenous Antigen-Endocytic or exogenous processing pathway Class II MHC molecules bind peptides and present to CD4+ T cells Endogenous Antigen-Cytosolic or endogenous processing pathway Class I MHC molecules bind peptides and present to CD8+ T cells
  14. 14. Uptake of exogenous antigens Membrane Ig receptor mediated uptake Phagocytosis YComplement receptormediated phagocytosis Pinocytosis Y Fc receptor mediated phagocytosis Uptake mechanisms direct antigen into intracellular vesicles for exogenous antigen processing
  15. 15. Exogenous pathway Cell surface Protein antigens Uptake In endosome EndosomesIncreasein acidity To lysosomesCathepsin B, D and L proteases are activated by the decrease in pH Proteases produce ~24 amino acid long peptides from antigens Drugs that raise the pH of endosomes inhibit antigen processing
  16. 16. MHC class II maturation and invariant chain In the endoplasmic reticulum Need to prevent newly Invariant chain stabilises MHC class II by synthesised, unfolded self non- covalently binding to the immature proteins from binding to MHC class II molecule and forming a immature MHC nonomeric complex
  17. 17. Class II associated invariant chain peptide (CLIP) Cell surface Endosomes Uptake( inv)3 complexes Cathepsin L degrades MHC Class IIdirected towards Invariant chain containing vesiclesendosomes by CLIP blocks groove in MHC fuse with antigeninvariant chain molecule containing vesicles
  18. 18. Removal of CLIP ?How can the peptide stably bind to a floppy binding site? Competition between large number of peptides
  19. 19. HLA-DM catalyses the removal of CLIP HLA-DM Replaces CLIP with a peptide antigen using a catalytic mechanism (i.e. efficient at sub- stoichiometric levels) Discovered using mutant cell lines that failed to present antigen HLA-DO may also play aHLA-DR HLA-DM role in regulating DM Sequence in cytoplasmic tail retains HLA-DM inMIIC compartment endosomes
  20. 20. Surface expression of MHC class II- peptide complexes Exported to the cell surface (t1/2 = 50hr) Sent to lysosomes for degradationMIIC compartment sorts peptide-MHC complexes for surface expression orlysosomal degradation
  21. 21. Peptide antigens produced in the cytoplasm arephysically separated from newly formed MHC class I ENDOPLASMIC RETICULUM Newly synthesised MHC class I molecules Peptides need access to the ER in CYTOSOL order to be loaded onto MHC class I molecules
  22. 22. Transporters associated with antigen processing (TAP1 & 2) Hydrophobic transmembraneLumen of ER domain PeptideER membraneCytosol Peptide Peptide Peptide antigens ATP-binding cassette from proteasome (ABC) domain Transporter has preference for >8 amino acid peptides with hydrophobic C termini.
  23. 23. Maturation and loading of MHC class I Peptide Peptide Peptide Endoplasmic reticulumCalnexin binds B2-M Tapasin, calreticulin, TAP Cytoplasmic peptidesto nascent binds and 1 & 2 form a complex with are loaded onto theclass I chain stabilises the floppy MHC MHC molecule and theuntil 2-M binds floppy structure becomes MHC compact
  24. 24. Fate of MHC class I Exported to the cell surfaceSent to lysosomes for degradation
  25. 25. Evasion of immunity by interference with endogenousantigen processing Peptide Peptide Endoplasmic reticulum Sent to lysosomes for degradation HSV protein blocks transport of viral peptides into ER
  26. 26. Evasion of immunity by interference withendogenous antigen processingNormally exported to the cell surface Adenoviral protein retains MHC class I in the ERSent to lysosomes for degradation
  27. 27. Presentation of NON PEPTIDE antigens T cells that express the γδ TCR that react with glycolipid antigens derived from bacteria such as Mycobacterium tuberculosis These non protein antigens are presented by members of the CD1 family of non classical class I molecules Genes encoding CD1 are located not within MHC
  28. 28. Summary• T and B cells recognise antigen differently• Antigen must be catabolised before T cells can recognise it• Antigen processing generates antigenic peptides• Exogenous antigen processing takes place in lysosomes• Endogenous processing is non-lysosomal• The mechanism of antigen processing depends upon the compartment in which the pathogen replicates• Endogenous and exogenous antigen processing both involve uptake, degradation, complex formation and presentation• Exogenous antigen processing uses invariant chain and HLA-DM• Endogenous antigen processing uses proteasomes and peptide transporters in antigen processing• Pathogens can evade immunity by disrupting antigen processing
  29. 29. Any Queries???????? ???????????Hope Not…………
  30. 30. THANKYOU........

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