Chapter 6 Immunology

• Antigen presentation


  Display of peptide on cell surface in association with MHC
• Antigen presentation functions


  • Arming effector T cells
  • Triggering their effector functions to attack pathogen-infected cells

  
• Topologically distinct compartments in cells


  • Cytoplasm/nucleus
  • Vesicular/extracellular
• Cytoplasm/nucleus


  Intracellular pathogens (viruses, some bacteria) bind to MHC class I and present to CD8+ T cells

  
• Vesicular/extracellular


  Extracellular pathogens, intravesicular pathogens bind to MHC class II and present to CD4+ T cells

  
• Pathways for antigen processing and presentation

  • 2 pathways

  
• Peptide generation from ubiquitinated proteins in the cytosol


  1. Proteasome

  2. Constitutive proteasome

  3. Immunoproteasome

  
• Peptide transport and processing before binding to MHC class I


  1. Transported by TAP into ER

  2. Further processed

  3. Bind to MHC class I

  
• MHC class I peptide loading in ER


  • Calnexin chaperone keeps alpha chain unfolded
  • Calreticulin/ERp57 chaperone binds complete MHC class I and tapasin
  • Tapasin bridges class I and TAP
  • Peptide binding stabilizes MHC
  • ERAAP trims peptide to 8-10aa

  
• Cross-presentation


  Dendritic cells present exogenous proteins on MHC class I to prime CD8 T cells

  
• Peptide:MHC class II complex generation


  1. In acidified endocytic vesicles

  2. From proteins obtained through endocytosis, phagocytosis, and autophagy

  
• Invariant chain


  Directs newly synthesized MHC class II molecules to acidified intracellular vesicles

  
• HLA-DM and HLA-DO


  Regulate exchange of CLIP for other peptides on MHC class II

  
• MHC can present many different types of peptides because it is polygenic and highly polymorphic
• MHC class I genes


  • HLA-A α chain
  • HLA-B α chain
  • HLA-C α chain

  
• MHC class II genes


  • HLA-DP α and β
  • HLA-DQ α and β
  • HLA-DR α and β

  
• Genes involved in immune function like complement and cytokines are encoded by the MHC

  
• MHC class I and class II genes


  • Highly polymorphic
  • 6 copies of MHC class I (a chain)
  • 6-8 copies of MHC class II (a and b chain)

  
• 1. 4 MHC class II molecules and 3 MHC class I molecules from each chromosome are expressed on the cell surface

  
• HLA is inherited as a unit (haplotype) and MHC expression is co-dominant
• Polymorphism and polygeny contribute to the diversity of MHC molecules expressed by an individual

  
• MHC polymorphism


  Affects antigen recognition by T cells by influencing peptide binding and T-cell receptor contacts

  
• MHC polymorphism extends the range of antigens to which the immune system can respond

  
• 1. cell recognition of antigens is MHC restricted

  
• MCH is composed of two subunits no matter if its MCH I or II 


  alpha and beta subunits
• MCH I or II is always on the surface of cells 


  usually holding self peptides
• Proteasome, 2 forms 


  degrades misfolded proteins
• Problem with proteasomes and peptides


  They are in the cytosol and get stuck until the binding domain arrives via transporter. Needs peptides
• Exogenous AG are expressed by MHC I


  usually only happens in MCH II
• MHC is a maker for itself


  for self vs non self
• How do peptides associate?


  MHC has alpha beta chains, co-translated in the ER, beta and alpha must interact and bind to each other to form MCH I
• Tapasin 


  functions as bridge between TAP and Erp57
• Peptides assoc with MHC I in the lumen, ERAAP trims peptides works in


  lumen. Once peptides bound to MCH I it now adopts mature conformation. No chaperone needed
• Why is exogenous AG expressed by MCH I ?(Cellular pathway)


  necrotic cells "epithelial" infected with virus, phagocytic cells take necrotic cell and phagocytose it by dendritic cells and ends up in a phagolysosome and breaks/destroys into small peptides
• Vesicular pathway


  peptides in phagolysosome by fusing to vesicle and transfer peptides and assoc with MHC I
• Endosomal pathway


  pH is not acidic but moving thru it gets more acidic
• Inactive protease activate


  in low pH
• MHC II variability is found in beta chain only


  binds peptides assoc, extending variability presenting to AG