Antigen presentation

1
Lecture 8

• Antigen presentation
• MHC restriction
• MHC genetics
• Cytotoxic CD8 T cell killing
• Subversion by viruses

Reading Chapter 3, and 6.13-6.14
2
T cells see presented antigen
Antigen presenting cell
CD8 T cells
20
13
14
15
16
17
19
18
4
5
3
2
9
6
8
7
1
11
12
Note the naïve T cell is not in killing mode the
ability to kill comes after antigenic stimulus
Note for both T and B cells antigen is a growth
factor
3
Review of the Zinkernagel-Doherty findings

• Killer T cells isolated from a previously
  infected mouse were used to kill different target
  cells in tissue culture.
• Say the mouse from which the killer cells came
  had MHC Class I molecules of type "k" and was
  infected with LCMV virus.
• The killer cells kill LCMV-infected cells from
  strains of mice carrying type "k" molecules
• The killer cells do not kill LCVM infected cells
  from mice that have type "d" MHC I molecules.
• Note that "k" and "d" are different natural
  variants of the same gene(s).

4
MHC proteins are polymorphic
Different variants of the gene occur in the
population so that most of use are heterozygous,
carrying two different allelic variants.
For example, there are over 200 different
variants of the human MHC class I gene HLA-A
5
Killer cells are specific for both the virus
peptide and the host MHC class I
Virus peptide
H-2Kd
H-2Kk
Mouse MHC class I on target cells
Host type
Different type
6
Figure A-38
Chromium release assay for T cell killing
From Janeway book
7
T cell recognition of a peptide-MHC complex
8
MHC class I and class II molecules are encoded by
several genes
Human Class I HLA-A, B, C Class II HLA-DR,DP, DQ
Mouse Class I H-2K,D, L Class II H-2I-A,E
9
Figure 3-28
10
Each T cell recognizes peptide associated with a
single self MHC molecule
11
T cell recognition of a peptide-MHC complex
12
Figure 3-29
MHC molecules have binding preference for
peptides carrying certain sequences. (Residues
in green point down, into MHC pockets)
13
Surprising, but true

• If a microbe had proteins such that none of its
  peptides can bind to MHC, it will be invisible to
  T cells!
• If a microbe mutates to avoid MHC binding of its
  peptides it would be a disaster!
• These considerations probably explain the
  polymorphism in MHC (large number of alleles
  within the populations)
• In each person there are also several different
  class I and class II genes (isotypes).
• This specificity of MHC binding also explains the
  link between antigen non-responsiveness to simple
  or small proteins and the MHC.

14
The human MHC class I genes
15
Figure 3-24 part 2 of 2
The human MHC class II genes
16
Figure 3-23
17
Because the polymorphic MHC molecules map near to
each other on human chromosome 6, one often talks
about "haplotypes" which refers to the collection
of linked gene versions. Typically, you inherit
one haplotype from your mother and one from your
father. Less frequently, a new haplotype is
formed by a crossover in germ cells of your
mother or father.
18
Figure 3-27
Other genes related to antigen presentation map
to the MHC
19
Figure 3-31
20
Figure 3-32 part 1 of 2
21
Figure 3-32 part 2 of 2
22
Figure 3-33 part 1 of 2
Over relatively short evolutionary time, rare
mutations are continually generating new variants
of MHC molecules that may be selected for.
23
Figure 3-33 part 2 of 2
24
Figure 3-34
Heterozygotes at all polymorphic MHC loci
Homozygous at one locus
Homozygous at 2 or 3
25
MHC molecules are essential
Bare Lymphocyte Syndrome--congenital deficiency
of either class I or class II molecules.
Patients lack killer cell or helper cell
responses and are prone to many types of
opportunistic infections.
26
Microbes often try to suppress antigen
presentation
Herpes Virus ICP-47 blocks TAP
function Adenovirus E1A inhibits transcription
of MHC class I genes E3 binds and retains class I
molecules in the ER Cytomegalovirus US3 protein
sequesters class I molecules in the ER US2 US11
proteins dislocates class I molecules from the
ER to cytoplasm HIV Vpu and Nef inhibit class I
expression
27
CD8 T cell mediated killing
Killing involves the generation of pores in the
plasma membrane of target cells and also the
initiation of programmed cell death by different
pathways
Perforin is a pore forming protein found in the
granules of activated, but not naïve, CD8 killer
cells. (It is related to complement component C9.)
28
Figure 6-28
29
Figure 6-29
30
Figure 6-30
31
Figure 6-31
32
Concepts

• MHC molecules are polymorphic and polygenic.
• MHC restriction occurs because T cells see a
  complex of foreign peptide and self-MHC.
• MHC molecules are semi-specific for peptide
  binding, and require "anchor residues."
• MHC allelic forms often have different peptidfe
  binding specificities and different T cell
  contact residues.
• MHC molecules are under intense evolutionary
  selection by microbes, favoring diversity.
• Microbes try other ways to suppress MHC mediated
  recognition.
• Activated CD8 T cells lyse target cells with the
  appropriate MHC class I /peptide complex.
• Killer cells induce programmed cell death
  (apoptosis) of targets.