MHC and

1
MHC and Antigen Presentation Chapters 6 7
Self-Test Questions Chap 6 A 1 5, 8
Note for A-5 know MHC I - III B D all Chap
7 A all B1 1, 4 8, 11, 12 B2-4 all C1
1,3 C2-4 all D all E 1, 3
2
What is the structure of MHC-I proteins? MHC-I a
chain ?-microglobulin Binding cleft Closed
ends Anchor residues Peptide may bend Expressed
in all nucleated cells
3
What is the structure of MHC-II proteins? MHC-II
a and ß chains Binding cleft open ends Anchor
residues Peptide lies flat Expressed only in
pAPC
MHC 3D Models
4
MHC proteins bind to peptides based upon general
properties
each MHC protein can bind to many different
peptides Shared properties of peptides binding
to two different MHC-II Shared properties of
peptides binding to a MHC-I
From Grey et al., Sci Amer November, 1989
5
How are MHC genes arranged on Chromosome 6? MHC
is polygenic Confusing terminology! HLA complex
in humans H-2 complex in mice Class II loci
DP, DQ and DR a and ß peptide genes Class I
loci A, B, C 1 gene each (ß-microglobin gene
is elsewhere) Class III loci misc other
genes Also, non-classic MHC-I and -II
genes e.g., DM, DO
6
Further polygenicity of MHC genes There are
multiple copies of some A and B genes! e.g.,
DRB1, DRB3, DRB9 DPA1, DPA2 and DPB1,
DPB2 DQA1, DQA2 and DQB1, DQB2, DQB3 -- many
pseudogenes also (e.g DRB2)
(Single gene for DRa peptide)
(Multiple genes for DRß peptide)
? gene
DR locus yields different MHC-II proteins
DRß1/DRa
DRß3/DRa
DRß4/DRa
7
MHC genes are also Polymorphic Different
people may possess slightly different alleles for
MHC peptides!
01 02 03 04 05 16
01 02 03
01 02 03
? gene
Broad allele classes
All yield
All yield
DR53
DR52
DR3 DR4 DR5 DR
HLA serotypes -- MHC proteins with distinct
antigenic properties
8
Alleles are further polymorphic
MHC-II DRß Loci
01 02 03 04 05 16
Minor alleles also exist within broad allele
0101 0102 0103 0122
0301 0302 0303 0341
Are all forms of HLA DR3 DR1
DRß name of MHC peptide subunit DR3 HLA
serotype family -- occurs in many different
polymorphic forms At the DNA level DRB1 a
locus of gene DRB103 broad allele
type DRB10301 minor allele type
9
How polymorphic is HLA?
Polygenetism is good Polymorphism is good for
the individual. Why? for the species. Why?
Good explanation Class II alleles Class
I alleles
10
MHC genes/serotypes are inherited as a set
(haplotype) 1 from mother, one from father
Crossing-over can create new haplotypes
11
Different HLAs predispose individuals toward
disorders
12
How many forms of HLA exist on cells? Genes
display codominance -- up to 6 forms of
MHC-I -- 12 forms of MHC-II Peptides from
different chromosomes can combine MHC
proteins 105 copies / cell 1018 in species
13
HLA polymorphism (HLA serotype variation) is the
primary cause of organ transplant rejection
How is HLA tissue typing performed? -- Determine
HLA antigens/genes of recipient and
potential donors HLA antigen typing -- use
lymphocytes -- serological (antibody) testing
-- genetic testing (e.g., PCR) Mixed
Lymphocyte Culture -- culture together donor
and recipient lymphocytes -- look for
immunological response from recipient cells
14
How is the mouse H-2 complex organized?
Mouse Strain Haplotype H-2 alleles H-2 alleles H-2 alleles H-2 alleles
Mouse Strain Haplotype MHC-I _ MHC-II_ MHC-I K IA IE D MHC-I _ MHC-II_ MHC-I K IA IE D MHC-I _ MHC-II_ MHC-I K IA IE D MHC-I _ MHC-II_ MHC-I K IA IE D
C3H k k k k k
BALB/c d d d d d
C57BL/6 b b b b b
A a k k k d
B10.A (3R) i3 b b d d
MHC-I at K, D and L -- K D ( L
sometimes) MHC-II at A and E loci -- IA IE
Mice can be bred -- Syngeneic e.g. H-2k,
H-2d -- both chromosomes have same haplotype
-- Congeneic C3H x BALB/C -? H-2d/k
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• How does MHC haplotype in influence recognition
  of antigens by TCRs?
• From H-2k mice the genes for a TH-cell TCR
  against a hen-egg lysozyme (HEL) peptide were
  transferred to H-2d , H-2k and H-2d/k mice. The
  mice were also transfected with the HEL gene,
  which is expressed only in the periphery (not
  thymus).
• HEL peptides will presented on which cells and
  on which MHC type?
• In mice of which haplotype(s) would the
  HELT-cells be released from the thymus?
• In mice of which haplotype(s) would the
  HELT-cells bind to the HEL peptides?
• Why was HEL-expressing virus used, instead of
  injecting HEL directly?

16

• Antigen Presentation
• -- chapter 7
• How are peptides loaded
• into MHC-II?
• Exogenous antigens
• Prof APCs
• Endolysosome
• Invariant chain (Ii) CLIP
• HLA-DM

17

• How are peptides loaded
• into MHC-I?
• Endogenous antigens
• All nucleated cells
• Protein synthesis
• Ubiquitin Proteasomes
• -- special immuno-proteosomes
• TAP transporters
• Chaperone proteins

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Antigen Cross presentation Exogenous AG on
MHC-I Possibly only certain DCs Why is this
necessary? strongest evidence for 2.
19
Other mechanisms of antigen presentation CD1
family (a-d) -- non-peptide antigens -- e.g.,
lipopeptides, glycolipids phospholipids Some
T-cells are CD1-restricted