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Antigen Processing and Presentation

Dr. Sarah Smith Email: [email protected] Phone: 555-123-4567 Drop by during office hours or make an appointment if you need help!

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36 views

Antigen Processing and Presentation

Dr. Sarah Smith Email: [email protected] Phone: 555-123-4567 Drop by during office hours or make an appointment if you need help!

Uploaded by

Min Kyu
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Download as PDF, TXT or read online on Scribd
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Lecture 10

Antigen Processing and


Presentation
Events in an Immune Response

From Janeway’s Immunobiology, 8th ed.


Cells of the Immune System

NK Cell
lymphocytes

APC (+B cells)


How do T cells recognize
antigens?
T Cell Recognition of Pathogens via
the MHC
The T cell receptor recognizes foreign peptides bound to MHC molecules
(unlike the BCR on B cells, which recognizes soluble antigens)

Peptide
MHC

The process by which antigens are presented to T cells in the context of


MHC is called antigen presentation
MHC Proteins bind Peptides

• Peptide binding groove formed by a b-sheet


“floor” and a-helical “walls”: a peptide sits in
the groove

• Each MHC molecule binds one peptide, but


the binding groove can accommodate many
different peptide sequences: promiscuous Peptides for MHC class I:
binding 8-10 a.a.

• Thousands of MHC molecules on a cell


surface can be presenting different peptides
to T cells

• Though many different peptides can bind in


the groove, there are restrictions on length
and sequence

Please note this correction! Peptides for MHC class II:


13-25 a.a.
Why do we need two types of MHC?

MHC class I MHC class II

• Binds to antigenic peptides that come • Binds to antigenic peptides that come
from inside the cell from outside the cell

• Proteins from intracellular pathogens • Extracellular pathogens are brought into


(e.g., viruses) are found inside the cell the cell by phagocytosis or endocytosis
and digested in the phagolysosome
• Presentation of intracellular peptides
on MHC class I leads to activation of • Presentation of extracellular peptides on
CD8+ T cells MHC class II leads to activation of CD4+ T
cells
• CD8+ T cells kill target cells
• CD4+ T cells help B cells make
antibodies
What happens when T cells
recognize antigens in the context
of MHC?
MHC:Peptide Complexes Activate T Cells

MHC
CD8 class I
T cell

CD4
T cell
MHC
Th1 subset class II

CD4
T cell MHC
class II
Th2 subset
How are the peptides “loaded”
into MHC molecules?
Sites of Proteins Degradation in the Cell
MHC molecules bind to peptides. How are these peptides generated?
1) Extracellular antigens are taken up by phagocytosis, and the proteins
are degraded into peptides in the phagolysosome
2) Intracellular proteins are degraded by the proteasome
Self proteins are degraded if they are misfolded or due to normal protein
turnover. Nonself (foreign) proteins are subject to the same processes.
The proteasome degrades self and
nonself proteins
• Proteins are continually synthesized by ribosomes on ER membranes
• Proteasome: large multi-catalytic protease complex that degrades
proteins in the cytosol (even when cells are not infected)
• Protein is introduced into the center of the “barrel” and digested by
proteases into peptides
• Both host (self) and viral (nonself) proteins are degraded
MHC Class I is loaded in the ER
Peptides are transported from the cytosol to
lumen of ER

TAP: Transporters associated with Antigen


Processing and Presentation

TAP-1 and TAP-2 transport peptides from TAP-1


cytosol to the ER lumen where newly TAP-2
synthesized MHC class I is found

• Mutations in TAP-1 or -2 can abolish


antigen processing by MHC class I and
cause MHC class I deficiency in humans

• “Empty” class I molecules stay in the ER

• Many viruses have gene products that


interfere with MHC class I Ag presentation
The MHC Class I Biosynthetic Pathway

• MHC class I is synthesized by


ribosomes on the ER
membrane

• b2 microglobulin associates
with MHC class I in the ER

• Antigenic peptides are


translocated into the ER via
TAP1/2

• Peptides are loaded onto MHC


class I in the ER

• MHC:peptide complexes traffic


to the plasma membrane for
presentation to T cells
MHC class I is on all
nucleated cells
Sites of Proteins Degradation in the Cell
MHC molecules bind to peptides. How are these peptides generated?
1) Extracellular antigens are taken up by phagocytosis, and the proteins
are degraded into peptides in the phagolysosome
2) Intracellular proteins are degraded by the proteasome
Self proteins are degraded if they are misfolded or due to normal protein
turnover. Nonself (foreign) proteins are subject to the same processes.
Extracellular antigens are degraded in
lysosomes and phagolysosomes

In lysosome,
phagolysosome

• Endosomes become increasingly acidic as they “mature” inside the cell and
fuse with lysosome – the change in pH activates proteases
• Degraded peptides associate with MHC class II molecules in these vesicles
Extracellular antigens are degraded in
Function = lysosomes and phagolysosomes
associates with
MHC class II in
the peptide-
•
binding groove The invariant chain binds to MHC class II in the ER and blocks the peptide-
binding groove so peptides cannot be loaded in the ER
• Once MHC class II reaches the peptide loading compartment, the invariant
chain (CLIP) is released
MHC Class I and Class II Pathways

MHC class II is only on


“professional” APCs MHC class I is on all
nucleated cells
MHC Polymorphism Affects Peptide
Binding

Regions of
variability
Genomic Organization of the MHC
• Each person has three genes encoding class I a chains that present Ag to
CD8+ T cells: HLA-A, HLA-B, HLA-C
• Each person has three pairs of genes encoding class II (a and b) chains that
present Ag to CD4+ T cells: HLA-DP, HLA-DR, HLA-DQ
• Thus, each person has three genes for MHC class I and three pairs of genes
(a and b) for MHC class II – most people are heterozygous for all genes

Class I Ag presentation:
HLA-A
Class II Ag presentation: HLA-B
HLA-DP HLA-C
HLA-DQ
HLA-DR
MHC Restriction of the TCR
MHC Restriction: T cell receptor is specific not only for a given peptide, but
for a unique combination of peptide and a particular MHC molecule
• The TCR recognizes a “surface” comprised of polymorphic residues of the
MHC molecule and the peptide

• MHC gene variants


are called alleles

• Protein products of
those alleles are
called MHC allotypes

Examples:

HLA-A*0201
HLA-B*5201
HLA-A*0201
Advantages of MHC Polymorphism

• Each pathogen expresses many proteins with different possible peptides


that can be presented

• MHC polymorphism allows an individual to present a larger pool of foreign


peptides to T cells, thus increasing the chances of an effective adaptive
immune response

• At the species level, having multiple combinations of alleles in the


population ensures that at least some individuals will be able to present a
given pathogen’s peptides (and survive an epidemic)

• MHC gene families further increases the chances of effective Ag


presentation
Office Hours/Discussion

Wednesdays from 4-5pm

Natural Sciences II, Room 4201

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