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Principles of ImmunologyAntigen Processing
3/2/06
“Doubt is often the beginning of wisdom.”M. S. Peck
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Word/Terms List
Cytosolic pathway Endocytic pathway Professional APC Proteasome Self-MHC Restriction
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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
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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
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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
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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
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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
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Two Pathways for Antigen Processing
Cytosolic and the endocytic pathways Cytosolic-Endogenous antigens Endocytic-Exogenous antigens
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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
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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
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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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