W12L20 - HLA and Antigen Presentation

Question 1

MHC

Answer 1

Genetic locus of immune function
Chromosome 6 in humans
Break down proteins of invaders and together move to surface to present Ag to T cells

Question 2

HLA

Answer 2

Human leucocyte antigen

• cell surface proteins encoded by genes within the MHC
• called HLA antigens
• alleles are alternate forms of any gene
• inherited co-dominantly

Question 3

T and B Cells - Recognition of Foreign Substances

Answer 3

B cells
- IgD & IgD on surface used as receptor
- recognise antigens in soluble form
- proteins, nucleic acid, polysaccharides, some lipids, chemicals
T cells
- recognise antigen displayed on cell surface in association with MHC molecule via TCR
- not soluble Ag
- fragment of protein

Question 4

Function of MHC

Answer 4

Generate antigen specific immune responses
Determine cells that are to be targeted for killing by T cells
Critical role in regulating immune responses by presenting antigen to TCR on T cells

Question 5

Minor Histocompatibility Antigens (mHAgs)

Answer 5

Other surface proteins can act as antigens

Complete matching for HLA leads to graft rejection, requirement for immunosuppressive therapy

Question 6

MHC Classes

Answer 6

Class 1
- cytotoxic T cells recognise peptides associated with class 1
Class 2
- helper T cells recognise peptides associated with class 2
- expressed only on B cells, dendritic cells, macrophages, monocytes
Class 3
- variety of genes, most related to immune function
- secreted and intracellular proteins
- tumor necrosis factor (TNF), complement, cytokines
- not very important to know

Question 7

MHC Class 1 and 2 Overview

Answer 7

Divided into classes related to structure, function and location within MHC
Trans-membrane protein
3 independent genes in class 1 - HLA-A, HLA-B and HLA-C
3 sets of genes in class 2 - HLA-DR, HLA-DG, HLA-DP

Question 8

MHC Class 1

Answer 8

Single gene coding for transmembrane glycoprotein formind 3 globular domains
- a1, a2 and a3
Linked to B2-microglobulin
a1 and a2 domains form peptide binding groove
- bind 8-9 aa peptides, synthesised inside cells
Variation in a1 and a2 domains determine peptide binding and antigenicity
Present antigen to cytotoxic T cells

Question 9

MHC Class 2

Answer 9

Consists of two transmembrane glycoproteins coded for by separate genes
- a and B
Form four domains
1. a1 and B1
- most distant from cell membrane, forms binding groove
- polymorphic region
- binds 12-17 aa peptides
2. a2 and B2
- nearest to cell membrane
- less variation
- binds to CD4 cells

Question 10

Differences between MHC Class 1 and 2

Answer 10

Class 1
- found on almost all cells
- responsible for presentation of antigens that originate within the host cell e.g. viral infection
- present to CD8 ells which are said to be MHC class 1 - restricted
Class 2
- found only on B cells, macrophages and other APCs
- present external antigens that are taken up and processed by APCs
- present to CD4 cells which are said to be MHC class 2 -restricted

Question 11

MHC Binding Site

Answer 11

Flexible at early intracellular stage
Binding site folds around peptide
Allows single MHC type to bind to many different peptides

Question 12

Exogenous Antigens

Answer 12

Antigens taken into cell by phagocytosis or endocytosis
MHC class 2 associated
Antigen taken up and contained in intracellular vesicle
Fuses with endosome or lysosome
Antigen broken down due to low pH
MHC class 2 formed in rough ER with CD74
MHC/CD74 complex moves to golgi then to acidic vesicle
Degradation of CD74 removes most but leaves part in binding groove (clip fragment)
Fusion with endosome/lysosome 
HLA-DM facilitates exchange of clip for antigen peptide
MHC class 2/peptide complex moves to surface for presentation

Question 13

Endogenous Antigens

Answer 13

Dervied from pathogens infecting cell (bacteria, viruses etc.)
MHC class 1 associated
Occurs in cytoplasm (not vesicle)
Proteasome cleaves proteins to peptides of roughly 15 aa
Cytosolic enzymes clave further to give peptides roughly 8-15 aa
Transported to ER by TAP-1 and 2
MHC class 1 synthesised, assemble with B2m
TAP transfers peptide to MHC class 1 molecule
MHC class 1/peptide complex moves via golgi to surface for presentation

Question 14

Response to MHC

Answer 14

All antigen will trigger CD4 responses since antigen is taken up by APC
Proteins derived from infections will trigger CD8 and CD4 response
Processing pathway important in determining CD4 or CD8 response

Question 15

Second Signal

Answer 15

T cells reactive to self peptides removed during differentiation in thymus
Pathogens produce ‘co-stimulator function’ or ‘second signal’ which isnt produced by self proteins
Second signal required for T cell activation