5. Antigen, antigen presentation and MHCs

Question 1

MHC abbreviation + definition

Answer 1

Major histocompatibility complex

“Immunogenic alloantigen proteins on cell surface”

Question 2

MHC-restricted recognition

Answer 2

T cell must interact with both the MHC molecule and the foreign peptide (co-recognition)

Question 3

MHC’s central role

Answer 3

Antigen presentation

• Genetically determined HLA molecules
• MHC I: HLA-A, -B, -C (present endogenous Ag’s)
• MHC II: HLA-DP, -DR, -DQ (exogenous Ag’s)

Question 4

Genetics MHC

Answer 4

• MHC I and MHC II loci closely linked
• Polygenic (HLA-A etc)
• Polymorphic (each locus has many diff. alleles)
• Co-dominantly inherited (both alleles of gene expressed)
• MHC III genregion lies between MHC I and II genregions, and codes for complement C3 convertases

Question 5

Genes of MHC I

Answer 5

HLA-A
HLA-B
HLA-C

Question 6

Genes of MHC II

Answer 6

HLA-DP
HLA-DQ
HLA-DR

Question 7

Combination of MHC polygeny and polymorphism

Answer 7

• Gives several different genes with similar function
• > individual produces a number of different MHC molecules
• Gives diversity within individual and population
• A single cell can display a large array of MHCs

Question 8

RBC MHC class

Answer 8

No MHC, because no nucleus

Question 9

MHC I structure

Answer 9

• Fixed pocket
• 8-9 AAs
• ENDOGENOUS peptide (virus, self, ic parasite, tumor)
• On all nucleated cells
• α1-3, β2microglobulin subunits

Question 10

MHC II structure

Answer 10

• Open cleft
• 11-25 AAs
• EXOGENOUS peptide (bacteria, lysosomal invaders)
• On antigen-presenting cells
• α1-2, β1-2 subunits

Question 11

Two main pathways of recieving antigens

Answer 11

1) Cytosol-derived (endogenous Ag’s)

2) Endosome/lysosome-derived (exogenous Ag’s)

Question 12

Where to find pathogens w/products in cell

Answer 12

• Cytosol (MHC I)

- Vesicles (MHC II)

Question 13

MHC+peptide

Answer 13

• Always appear together on cell surface
• Firm connection
• Both created and connected inside cell

Question 14

MHC synthesis location

Answer 14

RER (synthesized by ribosomes)

Question 15

Cuts pathogenic protein to peptide fragments

Where it cleaves

Answer 15

Proteosome

Cleaves next to hydrophobic and basic AAs

Question 16

Site of connection between MHC I and peptide

Fate of connected complex

Answer 16

RER

- Sent to golgi -> exocytosis to cell surface

Question 17

TAP

Answer 17

“Transporter associated with antigen processing”

• ATP-dependent peptide transport
• Selectivity: prefer >8 AA hydrophobic peptide with carboxyl ends
• Heterodimer: TAP-1 and -2
• Transports cytosolic peptide to RER for connection with MHC I

Question 18

Steps and location of endogenous processing

Answer 18

Every nucleated cells (MHC I)

1) Cytosolic antigens (viral, self, tumor etc)
2) Cleaved to peptides by proteosome
3) TAP inserts peptides into RER
4) Peptide+MHC I makes complex (chaperone used to cover binding site of MHC I, but has now disappeared)
5) Peptide-MHC-complex travels->golgi->exocytosis to surface of cell (to be recognized by cytotoxic T cells)

Question 19

Non-classical HLA molecules

Answer 19

HLA-E, -F, -G

• Less polymorphic
• Modulatory effects (e.g recognized by NKG2A inhibitory effector of NK cells)

Question 20

MHC II + exogenous peptide (steps of exogenous processing)

Answer 20

On antigen presenting cells (APCs)

1a) Exogenous peptide endocytosed into cell -> endosome
1b) MHC II synthesized in RER (connected to Ii chaperone) -> golgi -> lysosome (acidic -> degrade Ii -> CLIP - sitting in binding seat)
2) Fusion of endosome+lysosome
3) Degradation of pathogenic protein because acidic environment (lysosome)
- CLIP prevents formed peptides from binding MHC II
4) HLA-DM (RER->golgi->fuse with endosome+lysosome) will interact and release CLIP -> peptide can bind
5) Exocytosis of MHC II-peptide complex (not HLA-DM), displayed to Th cells

Question 21

Uptake of exogenous antigens (receptors)

Answer 21

• Phagocytes, DC, thymic epth. cells: any antigens (Lectin-R, Fc γ-R, complement R)
• B-cells: selected antigens (BCR)

Question 22

Ii

Answer 22

“Invariant chain” (chaperone)

• Prevent self peptide-MHC II binding
• Stabilizes + targets MHC II into lysosome
• Cleaved to CLIP in acidic environment

Question 23

CLIP

Answer 23

“Class II associated invariant chain peptide”

• Bound to groove of MHC II molecule
• Separated when HLA-DM arrives

Question 24

Goal of antigen presentation by different APCs

Answer 24

1) Dendritic cell
- To lymph node
- Present to naive T cell
- For priming: induce activation and determine differentiation way of T cell
2) B cells, macrophages
- Present to effector T cell
- Wants to get signals to facilitate their own maturation

Question 25

Cross-presentation of exogenous** antigens

Answer 25

Usually by DCs - Degraded in cytosol by retrotranslocation** - Bind to MHC I - Presented to naive CD8 T cells** - Activates CD8 T cell * * Exogenous Ag's are presented by endogenous pathway (in addition to exogenous pathway?) * * Needed to generate cytotoxic response to some viral/tumor Ag's

Question 26

Example of cross-presentation of exogenous Ag's

Answer 26

Viruses/tumors that do not appear in lymph nodes - Taken up as exogenous Ag's - Must be presented as endogenous Ag's for cytotoxic response - This is cross-presentation by DCs

Question 27

Cross-dressing of exogenous Ag's

Answer 27

Transfer of preformed peptide-MHC I complexes from infected cells to uninfected APCs without further processing needed - Transfer via trogocytosis or exosomes

Question 28

Special forms of Ag presentation

Answer 28

1) Cross-presentation 2) Cross-dressing 3) CD1-mediated presentation of lipid antigens to T-cells 4) Forcing incorrect Ag presentation by superantigens

Question 29

CD1-mediated presentation of (amphipathic) lipid antigens to T-cells

Answer 29

- CD1 structure similar to MHC I - CD1 groove larger, deeper, more hydrophobic - Lipid "legs" of Ag deeply inserted into groove -> more hydrophilic portions of ligand are exposed to TCR - Many diff. T cells bind these complexes

Question 30

DC roles in Ag processing and presentation

Answer 30

- Classical - Cross presentation - Cross dressing - Lipid presentation

Question 31

Forcing incorrect Ag presentation by superantigens

Answer 31

- Crossbridge between TCR β chain and MHC molecules without being processed -> Non-specific activation of T cells -> Polyclonal acivation (many diff T cells prod.) = weak, non-specific immune reaction to pathogen = and massive prod. of cytokines->systemic toxicity

Question 32

Example of diseases with HLA alleles

Answer 32

``` Mainly autoimmune diseases - Gluten-sensitive enteropathy - Narcolepsy - Psoriasis - Type I diabetes mellitus ++ ```

Question 33

Individual MHC allele polymorphism predicts:

Answer 33

- Resistance and susceptibility to infectious and autoimmune diseases - Compatibility of tissue transplants - Spontaneous abortion - Odour and mating preferences