Antigen Presentation to T Lymphocytes

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Chapter 5 Antigen Presentation to T Lymphocytes
ReviewTwo antigen-specific receptors the TCR
and the BCR. TCR sees antigens that were inside
cells and that are displayed on the surface by
MHC molecules.
MHC class I presents processed proteins that
were in the cytosol.MHC class II presents
processed proteins that were in endocytic
vesicles.
MHC class I presented-antigens are recognized by
CD8 T cells (CTL).MHC class II
presented-antigens are recognized by CD4 T cells
(TH).
Antigen Processing is the modification of native
proteins into peptides for presentation by MHC
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Basic cell structure
(ER)
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Inside of a cell, pathogens and their products
are found in either the cytosol or in vesicles
Mostly bacteria, common bacterial products (less
likely to be toxins and viruses), self junk
Mostly viruses but some bacteria
Bacteria, bacterial products, viruses (anything
that is antigenic)
Dendritic cell
and more (see chpt. 2)
after recognition by an appropriate T
cell
This slide is missing the very important antigen
presentation by dendritic cells Degrade in
vesicles peptides bind to MHC II, presented to
naïve CD4 T cells, activates naïve CD4 T cells
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How do cytosol peptides get associated with MHC
class I (and not with MHC class II)?
Peptides (made from proteins by proteosomes next
slide) are pumped from the cytosol into the
endoplasmic reticulum (ER) by transporters
associated with antigen processing (TAP) molecules
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In the cytosol, proteins are degraded into
peptides by proteasomes
2004 Nobel Prize in chemistry for the role of
ubiquitin in protein recycling
Proteasomes are multicatalytic protease complexes
made of 28 subunits
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Peptides are made from proteins in the cytosol,
transported into the ER, loaded into MHC class I
and transported to the surface of the cell
peptide
MHC class I
Which cells do this?
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Some viruses evade the immune system by
inhibiting or blocking antigen presentation by
MHC class I
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Peptides that are destine for MHC class II are
taken up from the outside of the cell and are
degraded into peptides in acidified endocytic
vesicles
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The invariant chain
Class II-associated invariant-chain peptide (CLIP)
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The invariant chain prevents MHC class II from
acquiring peptides too soon
Endosome containing degraded protein (i.e.,
peptides) fuses with endosome containing MHC
class II
Peptides binds to MHC class II. MHC class II
peptide are displayed on the cell surface
Which cells do this?
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More on the Major Histocompatibility Complex
Genetics and Function
MHC class I
MHC class II
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MHC class I and class II are polygenic (several
loci encoding products with essentially the same
function)
Class II
Class I
a chain
a chain
a chain
b2 microglobulin is not encoded in MHC
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A more detailed look at MHC
kb
More DNA than most bacterial genomes
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MHC class I and class II are polymorphic
variability at a gene locus at a frequency
higher than predicted by chance (i.e.,
variability of alleles in the species)
DPA, DQA and DRA are the MHC II a chain
DPB, DQB and DRB are the MHC II b chain
MHC I a chain
The number of known alleles at various MHC loci
seems to increases over time (why?)
MHC class I
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414 known HLA-A alleles in humans (previous
slide) but a maximum of 2 per person
for example, here is HLA class I A gene expression
Ay/g
Ab/r
MHC is polymorphic and expression is
co-dominant What does this meanfor you and your
species?
Although there are thousands of combinations in
the population, there are only 4 combinations
among siblings
Ab/g
Ar/y
Ab/y
Ar/g
At A there are 414 known alleles so there are
(414)2 171,396 pair combinations possible in
the species (although not all combinations exist)
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Lots of alleles in the species
In an individual, several non-allelic genes with
essentially the same function (B, C and A are all
MHC class I and present peptides to CTLs)
Ar
Br Cy Ap
Ay
Br Cy Ap
Because MHC loci are polymorphic, individuals are
rarely homozygous at any of the (polygenic) MHC
class I and II loci
All expressed on all nucleated cells (co-dominant)
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Why Polymorphism and Polygenism in MHC?
Polymorphism and polygenism in MHC make it
impossible for a pathogen to alter its antigenic
epitopes so that the epitopes cannot be presented
by a majority of the individuals in a population.
Most individuals have six MHC class I proteins
(and at least 6 MHC class II) so if one MHC
protein cannot present a pathogens antigens,
another MHC protein probably can. Each species
has thousands of way to present antigens from a
pathogen so, even if some individuals (or small
populations) cannot efficiently present some
antigens, the species is not at risk.
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Haplotype a linked set of genes associated with
one haploid genome
Common mouse MHC haplotypes
Skip this slide
H-2a
Kk
H-2b
H-2d
H-2f
Kd
We will commonly use the term MHCa or MHCaxb.
MHCa when both MHC haplotypes in an individual
are exactly the same (MHCa/a). MHCaxb as the
offspring when a MHCa individual is crossed with
an MHCb individual (MHCa/b)
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Haplotype a linked set of genes associated with
one haploid genome
Human specific term
If written as MHCa or HLAa, it is to be assumed
that the other allele is identical (i.e., MHCa/a
or HLAa/a and
Generic term
Class II Class I
DP DQ DR B C A
MHCa orMHCb orMHCa/b or MHCaxb MHCa/b
HLAa a/a a/a a/a a/a a/a
a/aHLAb b/b b/b b/b b/b b/b
b/bHLAa/b a/b a/b a/b a/b a/b
a/b
MHCa/a MHCa )
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MHC Restricted Recognition of Antigen by T cells
(MHC Restriction)
(MHC Restriction)
Target Cell used in In Vitro Killing Assay
MHCa no virus MHCa infected with virus X MHCb no virus MHCb infected with virus X
Source of CTLs
Mouse MHC haplotype Immune to virus X ?
CTL Killing of Target Cell in an In Vitro Assay?
No
MHCa

Yes
MHCa
No
MHCb

Yes
MHCb
Zinkernagal and Doherty, 1974 This figure is not
in the text
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Mapping the MHC restricted recognition of
antigens by CTLs
targets
H-2
Results of killing assay
H-2a
Killed by H-2d CTLs
Killed by H-2d CTLs
H-2d
It is okay to skip this slide
Not killed by H-2d CTLs
H-2k
Experiment Take CTLs from a virus-immunized H-2d
mouse and test on virus infected targets of the
H-2d, H-2a and H-2k haplotypes. Result H-2d and
H-2a cells are killed. H-2k cells are not
killed. Conclusion Killing maps to the right of
Ea (blue line).Other experiments show that CTL
killing is restricted to MHC class I All mice
in this experiment have the same background (non
MHC) genes
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The Zinkernagel Doherty experiment showed that
CTL killing is not only antigen specific, it is
specific for the MHC haplotypes of the
individual. Later experiments mapped killing
into MHC class I and TH activity into MHC class
II. Thus, TCRs are specific for the antigen
AND for allele-specific determinants of MHC
class I OR class II(i.e., MHC restricted-recognit
ion of antigen) Dual recognition vs. altered
self (new antigenic determinants NAD)
allele-specific
determinants
MHC polymorphism affects which antigens can be
presented and which T cells can recognize antigen
Although we have not shown experiments
demonstrating MHC restricted recognition of
antigens by TH1 and TH2 cells, TH recognition of
antigens is also MHC restricted (restricted to
allele-specific determinants of MHC class II)
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This shows one of an individuals two HLA (MHC)
loci
This shows both of an individuals two HLA
class I (MHC class I) loci and shows different
alleles at each of the three class I genes. The
uppercase letter is the gene the lowercase
superscript is the allele. HLA is on chromosome
6. Each of us has one chromosome 6 from mother
and another from father.
There will be some T cells that bind antigen
only when it is presented in association with Bx.
Other T cells will bind antigen only when
present in association with Aw. In all, there
are 6 different MHC class I proteins in an
individual and thus 6 ways to present antigen.
An individual T cell can bind antigen only when
it is presented by one of the 6 MHC proteins (the
T cell are restricted to allele-specific
determinants of MHC). The T cell are, of course,
also specific for the antigenic peptide. A T
cell receptor has 2 specificities, antigenic
peptide and allele-specific determinants of MHC.
Since MHC is polymorphic, how do the T cell
know what MHC type is expressed by self? The
answer to this question is yet to come.
This slide deals only with class I but
essentially everything is the same for T cells
that bind antigen presented by class II.
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How is genetic polymorphism generated? Gene
conversion in the germ line High crossover
rate When compared to similar events at other
loci, these germ line events are relatively
common in MHC however, they are still quite
rare. Somatic rearrangements are of no
consequence Over evolutionary time, many gene
conversion events to generate polymorphism in the
species
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Allelic variation in MHC occurs at the peptide
binding site and on the top/sides of the binding
cleft
MHC polymorphism in the peptide binding groove
explain the preference of different MHC proteins
for different sequence motifs. Polymorphisms on
the top of MHC show how TCRs recognize MHC-
allele-specific epitopes for restricted
recognition of antigens
For MHC class I, a1 and a2 domains are
polymorphic the a3 domain has relatively low
polymorphism b2microglobin is not
polymorphicFor MHC class II, a1 and b1 domains
are polymorphic a2 and b2 domains have
relative low polymorphism
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(No Transcript)
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There is extraordinary high immune reactivity to
allogeneic (same species, non-self) MHC. (thus
the name MHC). 1-10 of T cells will react to
any given allogeneic MHC (alloMHC).
How do you explain alloreactivity? Why?
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Superantigens
MHC
superantigen
TCR