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Principles of Immunology Antigen Processing 3/2/06

Principles of Immunology Antigen Processing 3/2/06. “Doubt is often the beginning of wisdom.” M. S. Peck. Word/Terms List. Cytosolic pathway Endocytic pathway Professional APC Proteasome Self-MHC Restriction. Self-MHC Restriction.

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Principles of Immunology Antigen Processing 3/2/06

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  1. Principles of ImmunologyAntigen Processing3/2/06 “Doubt is often the beginning of wisdom.” M. S. Peck

  2. Word/Terms List • Cytosolic pathway • Endocytic pathway • Professional APC • Proteasome • Self-MHC Restriction

  3. Self-MHC Restriction • T lymphocytes only respond to antigen that is bound to MHC molecules • Furthermore the MHC haplotype of the APC must be the same haplotype as that of the lymphocyte • This is the principle of Self-MHC restriction

  4. Experiment of Zinkernagel and Doherty • Self-MHC restriction first demonstrated with T helper (CD4) cells • Later shown that CD8 cells also are Self-MHC restricted • Used lymphocytic choriomeningitis virus in mice

  5. Experiment of Zinkernagel and Doherty • Mouse was primed with LCM via blood stream so Ag/lymphocyte interface occurred in spleen • Activated T cells were harvested • T cells would only respond to MHC presenting target cells of the same haplotype that also had endogenously processed LCM antigens on the surface

  6. Requirement for Ag Processing • APCs that are “fixed”, i.e. rendering the membrane impermeable are unable to process antigen for T helper cells • If fixation is delayed then Ag will have reached the surface of the APC and T helper will be activated • OR if the antigen is degraded and then exposed to APC, the APC can still effectively activate T helper

  7. Professional APCs • All nucleated cells can present Ag to CD8 cells • As such these cells become “target cells” because the CTLs will target them for destruction • Dendritic cells, macrophages and B lymphocytes are “Professional” antigens presenting cells • Professional APCs have MHC II and a co-stimulatory signal

  8. Two Pathways for Antigen Processing • Cytosolic and the endocytic pathways • Cytosolic-Endogenous antigens • Endocytic-Exogenous antigens

  9. Cytosolic Pathway • This pathway normally controls levels of proteins in cells • Sequence • Proteins targeted for proteolysis are complexed with ubiquitin • Ubiquitin-protein complexes are degraded within proteasomes • Peptides are picked up by TAP (Transporter antigen-associated processing) proteins

  10. Cytosolic Pathway • Sequence(cont’d) • ATP hydrolysis (energy requiring) step • TAP translocates peptides of 8-10 amino acids into rough endoplasmic reticulum • MHC molecule is assembled with peptide • Involves three chaperone molecules, calnexin,calreticulin and tapasin • Non bound peptides are degraded

  11. Endocytic Pathway • Mode of Ag entry determines which MHC complex it will bind with and which T lymphocyte will be activated • Sequence • MHC II molecules are blocked by association with invariant chain • MHC II complex travels through Golgi apparatus • Invariant chain is degraded leaving CLIP sitting in peptide groove of MHC II molecule • HLA-DM catalyses exchange of exogenous Ag peptide • Exogenous Ag has gone through ever more acidic endosomes that have degraded it to peptides of 13-18 amino acids

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