MHC and AG Presentation 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: allChap 7
A: allB1: 1, 4 – 8, 11, 12B2-4: allC1: 1,3C2-4: allD: allE: 1, 3
MHC and AG Presentation 2
What is the structure of MHC-I proteins?
MHC-I α chain
Β-microglobulin
Binding cleftClosed endsAnchor residuesPeptide may bend
Expressed in all nucleated cells
MHC and AG Presentation 3
What is the structure of MHC-II proteins?
MHC-II α and β chains
Binding cleftopen endsAnchor residuesPeptide lies flat
Expressed only in pAPC
MHC 3D Models
MHC and AG Presentation 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
MHC and AG Presentation 5
How are MHC genes arranged on Chromosome 6?
MHC is polygenic
Confusing terminology!HLA complex in humansH-2 complex in mice
Class II loci DP, DQ and DRα and β peptide genes
Class I lociA, B, C1 gene each(β-microglobin gene is elsewhere)
Class III locimisc other genes
Also, non-classic MHC-I and -II genese.g., DM, DO
MHC and AG Presentation 6
(Single gene for DRα peptide)
Further polygenicity of MHC genes
There are multiple copies of some A and B genes!
e.g., DRB1, DRB3, … DRB9DPA1, DPA2 and DPB1, DPB2DQA1, DQA2 and DQB1, DQB2, DQB3-- many pseudogenes also (e.g DRB2)
DR locus yieldsdifferent MHC-IIproteins
(Multiple genes for DRβ peptide)
γ gene
DRβ1/DRα DRβ3/DRα DRβ4/DRα
MHC and AG Presentation 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
γ geneBroad allele
classesDR53
= HLA “serotypes”-- MHC proteins with distinct antigenic properties
DR3 DR4 DR5…DR
DR52A
ll yield
All yield
MHC and AG Presentation 8
“DRβ” = name of MHC peptide subunit“DR3” = HLA serotype family
-- occurs in many different polymorphic forms…
At the DNA level“DRB1” = a locus of gene“DRB1*03” = broad allele type
“DRB1*0301” = minor allele type
*01*02*03*04*05…*16
Minor alleles also exist
withinbroad allele
Alleles are further polymorphic
*0101*0102*0103…*0122
*0301*0302*0303…*0341
MHC-II DRβ Loci
Are all forms of HLA… DR3 DR1
MHC and AG Presentation 9
How polymorphic is HLA?
MHC-I alleles
580
921
312
0 200 400 600 800 1000
HLA-A
HLA-B
HLA-CMHC-II Alleles
23
127
34
86
3
577
0 200 400 600 800 1000
HLA-DPα1
HLA-DPβ1
HLA-DQα1
HLA-DQβ1
HLA-DRA
HLA-DRB
Polygenetism is good Polymorphism is goodfor the individual. Why? for the species. Why?
Good explanation Class II alleles Class I alleles
MHC and AG Presentation 10
MHC genes/serotypes are inherited as a set (haplotype)1 from mother, one from father
Crossing-over can create new haplotypes
MHC and AG Presentation 11
Different HLAs predispose individuals toward disorders
Fraction of afflicted population with HLA AgFraction of normal population with HLA Ag
RR=
Associated RelativeAutoimmune Disorders HLA antigens RiskAutoimmune hepatitis DR3 14Primary Sjögren syndrome DR3 10Diabetes mellitus type 1 DR3 5Rheumatoid arthritis DR4 4Diabetes mellitus type 1 DR4 6Diabetes mellitus type 1 DR3 + DR4 15
Diseasesleprosy DR2tuberculosis DR2Chlamydia pneumoniae DR52aspergillosis DR15ragweed allergy DR5asthma, mite sensitive DR11
CancersKaposi's sarcoma DR5thyroid carcinomas DR8 + DR 11ovarian/cervical cancer DR10 + DR 11 + DR15
MHC and AG Presentation 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
MHC and AG Presentation 13
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
HLA polymorphism (HLA serotype variation) is the primary cause of organ transplant rejection
MHC and AG Presentation 14
How is the mouse H-2 complex organized?
MHC-I at K, D and L -- K & D (& L sometimes)
MHC-II at A and E loci-- IA & IE
I II II I (I)
I I I II II II
Mice can be bred: -- Syngeneic e.g. H-2k, H-2d
-- both chromosomes have same haplotype -- Congeneic
C3H x BALB/C - H-2d/k
Mouse Strain Haplotype
H-2 alleles
MHC-I _ MHC-II_ MHC-IK 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 and AG Presentation 15
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).
A. HEL peptides will presented on which cells and on which MHC type?
B. In mice of which haplotype(s) would the HELT-cells be released from the thymus?
C. In mice of which haplotype(s) would the HELT-cells bind to the HEL peptides?
D. Why was HEL-expressing virus used, instead of injecting HEL directly?
MHC and AG Presentation 16
Antigen Presentation -- chapter 7
How are peptides loaded into MHC-II?
• Exogenous antigens• Prof APCs• Endolysosome• Invariant chain (Ii) & CLIP• HLA-DM
MHC and AG Presentation 17
How are peptides loaded into MHC-I?
• Endogenous antigens• All nucleated cells• Protein synthesis• Ubiquitin & Proteasomes • -- special immuno-proteosomes• TAP transporters• Chaperone proteins
MHC and AG Presentation 18
Antigen “Cross presentation”
Exogenous AG on MHC-I
Possibly only certain DCs
Why is this necessary?
strongest evidence for 2.
MHC and AG Presentation 19
Other mechanisms of antigen presentation
CD1 family (a-d)-- non-peptide antigens-- e.g., lipopeptides, glycolipids
& phospholipids
Some T-cells are CD1-restricted
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