13 – linking innate & adaptive: Antigen processing Flashcards
MHC Class I presentation – require
cytosolic/endogenous processing
MHC Class II presentation require
exogenous processing
Endogenous pathogens & examples
Pathogen mediate their own entry into the cell
Ex: viruses/intracellular bacteria/intracellular parasites
Cytosolic pathogens (endogenous pathogen) pathway
Degraded in cytosol
Peptides bind to MHC class I
Presented to Effector CD8 T cells
Peptides are generated by… how does this work? tagged by?
protease complexes: Proteasomes
Ubiquitin proteins = tag intracellular proteins for degradation
Tagged proteins = fed into proteasomes
Self-peptides are presented on MHC class …
Class I
…serve as signal for recognition by proteosomes
Polyubiquitination
Polyubiquitinated proteins –
fed into proteasome & degraded
Gets peptide fragments
pathway of presenting onto MHC class I
step 1:
MHC class I folding
Partly folded MHC I α chain held in place by chaperone – calnexin
β2 microglobulin not bound yet
pathway of presenting onto MHC class I
step 2:
MHC class I complex released from calnexin, proteins translating in cytosol
MHC I α chain released from calnexin
MHC I α chain & β2 microglobulin interact in presence of additional chaperones
-Calreticulin
-ERp57
Partly folded MHC I binds to chaperone (Tapasin) to link it to TAP
Proteins are also being translated in cytosol
-some are ubiquitinates
pathway of presenting onto MHC class I
step 3:
polyubiquitinated proteins degraded & brought into ER
Polyubiquitinates proteins get degraded by proteasome in cytosol
Peptide fragments are brought into ER by TAP
-TAP pumps peptide fragment in ER
ERAAP trims peptides that are too long to bind to MHC
Peptide binding to MHC I – allow MHC to be properly folded
pathway of presenting onto MHC class I
step 4:
folding complete of peptide bound to MHC & targeted to cell surface
Peptide binds to peptide binding groove of MHC I
MHC I folding complete
pMHC-I released from TAP
pMHC-I targeted for cell membrane
Exogenous pathogens
Pathogens are taken up by immune cells by a form of engulfment (phagocytosis or endocytosis)
Then processed to be presented onto MHC II molecules
Entry of exogenous pathogens is mediated by & examples
immune cells
Extracellular bacteria/parasites/fungi
Exogenous pathway
Peptides are generated from
internalized antigens in endocytic vesicles
Particles are taken in within endosomes
Endosomes are fused with lysosome – phagolysosome
Contents are degraded
Simultaneously – … are …
MHC class II molecules are produced & exported from ER in vesicles
Peptides are generated in acidified vesicles
Lead to proteolytic activity – degrade antigen to peptide fragment
MHC II molecules, how
MHC II formed in ER
Invariant chain (li) binds to peptide groove
role of invariant chain (li)
li guides transport of class II MHC molecules to endocytic vesicles
li uses sorting signals in cytoplasmic tail to direct MHC class II molecule
Containing vesicles to peptide-containing endocytic compartments
li prevents peptides from binding to groove too early in ER
Clip & li
Li is first degraded by proteolytic activity within endocytic compartments to CLIP - class II-associated invariant chain peptide
Peptide loading onto MHC-II
step 1:
invariant chian (li) in complex with MHC class II
Complex of li & MHC class II – peptides can’t bind
In ER & in endocytic vessel
Peptide loading onto MHC-II
step 2:
li degraded resulting in CLIP
Due to acidification – li is cleaved –> leave CLIP bound to MHC II
Peptide loading onto MHC-II
step 3:
Fusion with vesicle containing degraded peptides
Peptides still cant bind MHC II because of CLIP blocking it
Peptide loading onto MHC-II
step 4:
HLA-DM releases CLIP & allows peptide binding to MHC class II
HLA-DM – human leukocyte antigen-DM binds MHC II
Binds to & stabilizes MHC class II molecules & releases CLIP – peptides can bind
Peptide can bind to peptide-binding groove of MHC II
pMHC-II targeted to cell surface
Summary
explain HLADM
MHC class II-like molecules
No peptide binding groove – similar structure
Found predominantly in late endosomal compartments with li & MHC II molecules
Where do peptides come from?
class I vs II
Endogenous (viruses, self-proteins)
Exogenous (bacterial toxins, phagocytosed bacteria)
What processes antigen?
class I vs II
By proteosome
By proteases in acidified vesicles
What molecules help load peptide onto MHC?
class I vs II
From cytosol to ER by TAP
HLA-DM catalyzes peptide loading
Which molecular chaperones are involved?
class I vs II
Calnexin, tapasin
Invariant chain
What is the loading compartment?
class I vs II
Endoplasmic reticulum
vesicle
