Reju

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Antigen Processing and Presentation

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Reju

  1. 1. ANTIGEN PROCESSING AND PRESENTATION<br />V.Reju<br />
  2. 2. ANTIGEN PROCESSING<br />The conversion of native proteins to peptides which can combine with MHC molecules<br />
  3. 3. ANTIGEN PRESENTATION<br />The course of formation and display of peptide-MHC complexes on the surface of APCs and the course of peptide MHC complexes recognition by T cells<br />
  4. 4. ANTIGEN PRESENTING CELLS<br /> A group of cells that play important role in immune response which can uptake ,process antigens and present peptide-MHC complexes to T cells <br />
  5. 5. GENERAL PROPERTIES OF APC<br />Capacity to uptake proteins<br />Ability to process proteins to peptides<br />Capacity to present peptides depends on type of MHC molecules expressed<br />Must express co-stimulatory signals for T cell stimulation<br />
  6. 6. PROFESSIONAL APCs<br /><ul><li>Dendritic cells
  7. 7. Macrophages
  8. 8. B cell</li></li></ul><li>NON- PROFESSIONAL APCs<br /><ul><li> Fibroblast
  9. 9. Thymus epithelial cells
  10. 10. Thyroid epithelial cells
  11. 11. Pancreatic beta cells
  12. 12. vascular endothelial cells</li></li></ul><li>DENDRITIC CELLS<br />First found by Steinman in 1973<br />Cultured in vitro in 1993 by Inaba<br />Generated from bone marrow in presence of cytokine granulocyte-macrophage colony stimulating factor<br />Can stimulate naive T cell <br />
  13. 13. WHY DENDRITIC CELLS ARE CONSIDERED AS MOST EFFECTIVE APC?????? <br />
  14. 14. MACROPHAGE ( MΦ)<br />First identified APC<br />Differentiated from monocyte in blood<br />Cannot stimulate naïve T cell<br />Capture antigens by phagocytosis ,pinocytosis and receptor mediated phagocytosis<br />
  15. 15. B CELLS<br />Originates in bone marrow <br />Mature B cell co-express IgM and IgD on their cell surface <br />
  16. 16. SELF MHC RESTRICTION OF T CELL<br />CD 4+ and CD 8+ cells recognize antigen only in presence of MHC<br /><ul><li> MHC I + peptides » CD 8+ T Cell
  17. 17. MHC II + peptides » CD 4+ T Cell</li></li></ul><li>Self-MHC I restriction <br />
  18. 18. Self-mhc ii restriction<br />
  19. 19. TWO PATHWAYS BASED ON ANTIGEN<br />
  20. 20. Antigen presentation by class I mhc<br />
  21. 21. P<br />Mhc class i<br />α2<br />α1<br />α3<br />* α1, α2, α3 are the domains of α chain,45kDa<br />* β2 microglobulin ,12kDa,small soluble domain<br />* P->Peptide-binding site<br />* T->Hydrophobic Transmembrane segment<br />* ER.M->Endoplasmic reticulum membrane<br />* C->Hydrophilic Cytoplasmic tail<br />β2<br />ER.M<br />T<br />C<br />
  22. 22. α-chain<br />Encoded by HLA-A,B,C genes<br />Consist of carboxyl-terminal short domain, transmembrane hydrophobic region,extracellular domain,aminoterminal signal peptide<br />α-chain consists of α1,α2,α3 domain<br />α1 and α2 forms a groove for the peptide-binding site<br />
  23. 23. β2-microglobulin<br />Interacts non-covalently with α3 domain<br />Encoded by highly conserved gene located on a different chromosome<br />Required for the expression of Class I molecules on cell membrane<br />
  24. 24. ANTIGEN PRESENTATION BY MHC I<br />4.Presenting to CD8+T cells<br />1.Processing of endogenous Ag<br />2.Transporting of antigen peptide into ER<br />3.Peptide loading of class I MHC molecules<br />
  25. 25. 1.PROcessing of endogenous Antigen<br />20S<br />Endogenous antigens are degraded by Proteasome(26S)<br />Consist of 20S proteasome(a catalytic core) and 19S particle(a regulatory component)<br />Degradation of protein requires ubiquitin molecule <br />Cytokine(IFNγ) enhance the production of LMP2, LMP7 and MECL-1(LMP10) and replace β1,β5,β2 respectively to form IMMUNOPROTEASOME<br />β<br />α<br />α<br />β<br />19S<br />
  26. 26. Ubiquitination of protein<br />Ub<br />E1<br />ATP<br />Ub<br />ADP + Pi<br />E1<br />Ub-Ubiquitin<br />E1-Ubiquitin-activating enzyme<br />E2-Ubiquitin-conjugating enzyme<br />E3-Ubiquitin ligase<br />E2<br />Ub<br />Ub<br />E1<br />Ub<br />E3<br />Ub<br />Ub<br />Proteasome<br />Ub<br />Peptides<br />Polyubiquitinated protein<br />
  27. 27. 2.Transporting of antigen peptide into er<br />TAP( Transporter associated with antigen processing)<br />TAP2<br />TAP1<br />Consisting of TAP1 and TAP2<br />ATP dependent transporter<br />Selective transporting (8-11aa)<br />
  28. 28. Hydrophobic<br />transmembrane<br />domain<br />Lumen of ER<br />Peptide<br />ER membrane<br />TAP-1<br />TAP-2<br />Cytosol<br />ATP-binding cassette<br />(ABC) domain<br />Peptide antigens<br />from proteasome<br />Transporters associated with antigen processing (tap1 & tap2)<br />
  29. 29. Peptide<br />TAP-1<br />TAP-2<br />Endoplasmic reticulum<br />3.Peptide loading of class I mhc molecules<br />Nascent class I chain<br />Class I MHC<br />ERP57<br />β2-M<br />Calnexin<br />Tapasin<br />Calreticulin<br />2-M binds and stabilises floppy MHC<br />Tapasin, calreticulin,ERP57, TAP 1 & 2 form a complex with the floppy MHC<br />Calnexin binds<br />to nascent<br />class I chain<br />Until 2-M binds<br />Cytoplasmic peptides are loaded onto the MHC molecule and the structure becomes compact<br />β<br />
  30. 30. 4.Presenting to cd8+t cells<br />Tc Cell<br />TCR<br />Antigen peptide-class I MHC molecules presented on cell membrane by exocytosis<br />P<br />α2<br />CD8<br />α1<br />α3<br />β2<br />C.M<br />T<br />C<br />
  31. 31. Antigen presentation by class ii mhc<br />
  32. 32. 1. Capture of exogenous antigen<br />2. Processing of antigen<br />3. Synthesis and transportation of class II molecule<br />4. Association of processed peptide with MHC II<br />5. Presenting to CD4+ T cells<br />EXOGENOUS OR ENDOCYTIC PATHWAY<br />
  33. 33. Endocytosis<br /> Phagocytosis<br /> Pinocytosis<br /> Receptor mediated endocytosis<br />Form Endosome <br />CAPTURE OF EXOGENOUS ANTIGEN<br />
  34. 34. Processing of antigen<br />Takes place in endosome(MIIC/CIIV) and lysosome<br />Protease – Cathepsin cleaves peptides from Protein<br />Cell surface<br />Endosome<br />Peptides in endosome<br />
  35. 35. Mhc ii molecule<br />α1<br />β1<br /> MHC II is synthesized in ER<br />Folding and assembly is aided by <br />ER resident chaperon- calnexin <br />INVARIANT CHAIN ( Ii )<br /> Ii is a trimer ,each binding to <br />newly formed MHC II<br />Transport to GA through ER vesicle<br /> Fusion with MIIC containing <br />HLA-DM ,cathepsin S<br />α2<br />β2<br />
  36. 36. Association of processed peptide with MHC II<br />Invariant chain degradation leaving <br />CLIP by proteolytic enzyme Cathepsin S<br />Replacement of peptide in place of <br /> CLIP by HLA -DM<br />
  37. 37. Presenting to CD4 T cells<br />Formed peptide-MHC molecule is presented on surface of APC<br /> TCR binds with α1,β1 of MHC II and peptide<br />
  38. 38. Thank you<br />

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