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MHC Molecules Part 2

Dr. Rabiul Haque

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Pathway of Antigen Processing & Presentation
• Proteins that are present in the cytosol are degraded by proteasomes
to provide peptides that are displayed on class I MHC molecules.
• Proteins that are ingested from the extracellular environment and
sequestered in vesicles are degraded in lysosomes (or late
endosomes) to generate peptides that are displayed on class II MHC
molecules.
• Peptide binding to MHC molecules occurs before they are expressed
to cell surface.

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Pathway of Antigen Processing & Presentation
Occurs In Following Steps
• Digestion of the cytosolic proteins by the proteasomes.
• Transport of peptides from the cytosol to endoplasmic reticulum.
• Assembly of "Peptide–Class I MHC Complexes" in endoplasmic
reticulum.
• Surface Expression of Peptide–Class I MHC Complexes.

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Digestion of Cytosolic Proteins by
Proteasomes.
• Where do the microbial proteins present in the cytosol come from?
• From microbes (typically viruses) that replicate in the cytosol.
• From extracellular bacteria that injects proteins into the cytosol.
• From antigens that are internalized into phagosomes but have
escaped into the cytosol. (e.g. Listeria monocytogenes).
• Proteins synthesized on free ribosomes that are improperly folded
are also degraded in proteasomes.
• Nuclear proteins of damaged cells or tumor cells are also degraded
in proteasomes.
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Proteasomes
• Proteasomes are large multiprotein enzyme complexes and they
have a broad range of proteolytic activity.
• They are found in the cytoplasm and nuclei of most cells.
• It looks like a cylinder composed of a stacked array of two inner β
rings and two outer α rings.
• Each ring is composed of seven subunits, with a cap-like structure
at either end of the cylinder.
• The proteins in the outer α rings are structural and do not have
proteolytic activity.
• In the inner β rings, three of the seven subunits (β1, β2, andβ5)
are the catalytic sites for proteolysis.
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Transport of Peptides From the Cytosol to the
Endoplasmic Reticulum
• Peptides generated by proteasomes in the cytosol are translocated
into the Endoplasmic Reticulum by a specialized transporter.
• A dimeric protein located in the ER membrane called "Transporter
associated with Antigen Processing(TAP)" mediates the delivery.
• TAP optimally transports peptides ranging from 8 to 16 amino
acids in length.
• In the endoplasmic reticulum, newly synthesized class I MHC
molecules are available to bind with the transported peptides.

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Assembly of Peptide–Class I MHC Complexes
in the Endoplasmic Reticulum
• The TAP protein associates with a protein called Tapasin on the
luminal side of the ER membrane.
• Tapasin has affinity for newly synthesized empty class I MHC
molecules.
• Tapasin brings the TAP transporter into a complex with the class I
MHC molecules that are waiting for the arrival of peptides.
• Peptides translocated into the ER bind to class I MHC molecules
that are associated with the TAP dimer with the help of tapasin.

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Assembly of Peptide–Class I MHC Complexes
in the Endoplasmic Reticulum
• Class I α chains and β2-microglobulin are synthesized in the ER.
• Membrane chaperone calnexin and the luminal chaperone
calreticulin helps in appropriate folding of nascent α chains.
• Newly formed empty class I MHC dimers remain linked to the TAP
complex.
• Empty class I MHC molecules, TAP and tapasin are part of a larger
peptide loading complex.

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Assembly of Peptide–Class I MHC Complexes
in the Endoplasmic Reticulum
• ER-resident aminopeptidase (ERAP) trims the peptide entering ER
through TAP as well as peptides produced inside the ER into
appropriate size for MHC binding.
• Once class I MHC molecules are loaded with peptide, they no
longer have the affinity for tapasin.
• Peptide–class I complex will be released.
• Then it is able to exit the ER and be transported to the cell surface.

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Assembly of Peptide–Class I MHC Complexes
in the Endoplasmic Reticulum
• Peptides transported into the ER preferentially bind to class I but
not class II MHC molecules. Why?
• Newly synthesized class I molecules are attached to the luminal
aspect of the TAP complex
• As the peptides are transported into the ER by TAP, they are
captured rapidly by class I MHC molecules attached with TAP.
• Peptide-binding grooves of newly synthesized class II molecules
in the ER are blocked by a protein called the invariant chain.

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Surface Expression of Peptide–Class I MHC
Complexes
• Class I MHC molecules with bound peptides in the groove are
structurally stable.
• Stable peptide–class I MHC complexes move through the Golgi
complex and are transported to the cell surface in exocytic
vesicles.

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Class II Pathway of Antigen Processing &
Presentation
• Proteolytic degradation of internalized proteins in late endosomes
and lysosomes.
• Binding of peptides to class II MHC molecules in this vesicular
compartment.
• Expression of Peptide–Class II MHC Complexes on Cell Surface.

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Proteolytic Degradation of Internalized Proteins in Late
Endosomes and Lysosomes.
• Where do the class II MHC associated peptides come from?
• From protein antigens that are digested in endosomes and
lysosomes in APCs.These include:
• Extracellular proteins captured by endocytosis, pinocytosis
or phagocytosis.
• Cell surface proteins that are being endocytosed for
degradation.
• Intracellular proteins (membrane-bound, vesicular, or
cytosolic) during the process of autophagy.

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Proteolytic Degradation of Internalized Proteins in Late
Endosomes and Lysosomes.

• Once internalized, protein antigens become localized in
intracellular membrane-bound vesicles called endosomes.
• Particulate microbes are internalized into vesicles called
phagosomes.
• Endosomal pathway of intracellular protein traffic then
communicates with lysosomes.
• Lysosomes are denser membrane-bound enzyme-containing
vesicles.
• Phagosomes may fuse with lysosomes and produce vesicles called
phagolysosomes or secondary lysosomes.
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Proteolytic Degradation of Internalized Proteins in Late
Endosomes and Lysosomes.

• Internalized proteins are degraded enzymatically in late
endosomes and lysosomes.
• This generates peptides that can bind to the peptide-binding
grooves of class II MHC molecules.

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Binding of Peptides to Class II MHC
Molecules in Vesicular Compartment.
• Class II MHC molecules are synthesized in the ER.
• Then they are transported to endosomes with an associated
protein, the invariant chain (Ii).
• Invariant chain occupies the peptide-binding grooves of the newly
synthesized class II MHC molecules and prevents it from accepting
peptides.
• Class II MHC molecules cannot bind and present peptides they
encounter in the ER due to their attached invariant chains.
• Invariant chains also directs newly formed class II MHC molecules
from the trans-Golgi to late endosomes and lysosomes.

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Binding of Peptides to Class II MHC
Molecules in Vesicular Compartment.
• Once inside the endosomal vesicles, the invariant chain dissociates
from class II MHC molecules by the combined action of proteolytic
enzymes and the HLA-DM molecule.
• Now peptides derived from protein antigens can bind to the
available peptide-binding grooves of the class II molecules.

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Expression of Peptide–Class II MHC
Complexes on Cell Surface
• The bound peptides stabilize Class II MHC molecules.
• The Stable peptide–class II complexes are delivered to the
surface of the APC.

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Importance of MHC Molecules
• Antigen recognition by T cells is dependent on association of the
antigen with either class I or II MHC molecules.
• Many autoimmune diseases occur in individuals who carry certain
MHC genes.
• Success of organ transplant depends on compatibility of MHC
molecules of the donor and recipient.

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Autoimmune Disease HLA Allele

Rheumatoid arthritis DR4

Systemic lupus erythematosus DR2/DR3

Insulin-dependent diabetes mellitus DR3/DR4

Multiple sclerosis, Goodpasture’s DR2

Ankylosing spondylitis, inflammatory B27
bowel disease, reactive
arthritis, psoriasis

Graves disease B8

Celiac disease DQ2 or DQ8
Thank You!

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