Principles of Immunology Antigen Processing 3/2/06

Principles of ImmunologyAntigen 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 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 co-stimulatory 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 13-18 amino acids