Transcript Antigen Processing 03/02/06

Principles of Immunology
Antigen Processing
3/2/06
“Doubt is often the beginning of wisdom.”
M. S. Peck
Word/Terms List
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Cytosolic pathway
Endocytic pathway
Professional APC
Proteasome
Self-MHC Restriction
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
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
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
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
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 costimulatory signal
Two Pathways for
Antigen Processing
 Cytosolic and the endocytic pathways
 Cytosolic-Endogenous antigens
 Endocytic-Exogenous antigens
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
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
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 1318 amino acids