L6: Major Histocompatibility Complex

Question 1

What do T cells recognize?

Answer 1

Processed antigen fragments presented by MHC molecules

Question 2

What do helper CD4+ T cells recognize?

Answer 2

Processed antigen fragments presented by MHC class II molecule

Question 3

What do cytotoxic CD8+ T cells recognize?

Answer 3

Processed antigen fragments presented by MHC class I molecule

Question 4

What gene complex encodes the MHC proteins in humans?

Answer 4

Human leukocyte antigen (HLA)

Question 5

What loci is human MHC Class I encoded by?

Answer 5

Loci HLA-A, HLA-B, and HLA-C

Question 6

What loci is human MHC Class II encoded by?

Answer 6

HLA-DR, DQ, and DP

Question 7

What are some other genes mapped within the MHC region?

Answer 7

Factor B
Complement proteins
TAP1 and TAP2
Cytokine genes (such as TNF)
Some non-classical MHC class I genes: HLA-E, HLA-F, and HLA-G

Question 8

What are the 2 striking characteristics of the MHC system?

Answer 8

1. Extremely polymorphic: at each of the loci, there are numerous alternative alleles
2. These, as far as expression of HLA molecules on surface of cells that express them, will be co-dominantly expressed

Question 9

What is the inheritance pattern of HLA?

Answer 9

Standard Mendelian segregation

Recombination can occur

Question 10

In MHC Class I, which loci is most polymorphic?

Answer 10

B

Question 11

In MHC Class II, which loci is most polymorphic?

Answer 11

DRB

Question 12

Describe the general structure of MHC Class I molecules

Answer 12

Heavy α

chain that is non-covalently associated w/ small chain called β-2 microglobulin

Question 13

What aspect of MHC class I molecules is invariant?

Answer 13

β-2 microglobulin

α3 domain

Question 14

What forms the peptide binding cleft in MHC class I molecules?

Answer 14

α1 and α2 domains

Question 15

Where on MHC class I does the receptor recognize it?

Answer 15

α3 domain

Question 16

Describe the general structure of MHC class II

Answer 16

2 heavy chains: an α chain and a β chain

Question 17

What forms the peptide binding cleft in MHC class II molecules?

Answer 17

α1 and β1 regions

Question 18

At any given time, how many peptides can a peptide binding cleft bind?

Answer 18

1 peptide

Question 19

What is the nature of the peptide-binding cleft of MHC class I molecules? Class II molecules?

Answer 19

Class I: closed at both ends

Class II: open at both ends

Question 20

What is the general size of bound peptides of MHC class I molecules? Class II molecules?

Answer 20

Class I: 8 - 10 amino acids (9 is ideal)

Class II: 13 - 18 amino acids

Question 21

What are the peptide motifs involved in bind to MHC class I molecule? Class II molecule?

Answer 21

Class I: Anchor residues at both ends of peptide; generally hydrophobic carboxyl-terminal anchor

Class II: Anchor residues distributed along the length of the peptide

Question 22

What allows MHC class II molecules to bind larger peptides?

Answer 22

Peptide binding cleft is open

Question 23

What has to be the same in all the peptides that can bind a specific MHC class I molecule?

Answer 23

The anchor residues must be the same for them to bind the same MHC class I molecule

Question 24

What are the anchor residues of MHC class I molecules?

Answer 24

2 and 8 positions

Question 25

What are the anchor residues of MHC class II molecules?

Answer 25

Anchor residues not so well defined

Question 26

Where does allelic variation occur within MHC molecules?

Answer 26

In peptide binding pockets For class I, variation is found in alpha 1 and apha 2 domains (alpha 3 is invariant) For class II, variation is found mostly in beta 1 domain

Question 27

How is T cell recognition of antigens restricted?

Answer 27

It is MHC restricted T cell receptor has a specific recognition area that will bind self-MHC that some processed peptide Both the peptide and the MHC molecule need to be correct for recognition to occur

Question 28

Where are MHC class I molecules distributed (in humans)?

Answer 28

All nucleated cells Platelets Not on RBCs (which is fortuitous in blood transfusion)

Question 29

Where are MHC class II molecules distributed (in humans)

Answer 29

Primarily on cells that can act as antigen-presenting cells B cells Macrophages Dendritic cells Activated T cells (human)

Question 30

Are all cells that express class II molecules also going to express class I molecules?

Answer 30

Yes

Question 31

Are all cells that express class I molecules going to express class II molecules?

Answer 31

Not necessarily

Question 32

What is the exception to the rule of T cells only recognizing self-MHC w/ some foreign antigenic peptide attached to it?

Answer 32

T cell alloreactivity

Question 33

T cell alloreactivity

Answer 33

Ability of T cell in culture dish or in vivo (in certain conditions) to recognize foreign, or non-self, MHC Only time this could happen in vivo is in case of organ transplantation where organ is of different MHC than you are Could also happen during a blood transfusion if WBCs are part of blood product that you receive Or during pregnancy This is the basis of what happens in graft rejection

Question 34

What are the situations in which allogenic T cell reactivity occurs in vivo?

Answer 34

Organ transplant Blood transfusion if WBCs are part of the blood product During pregnancy

Question 35

Superantigen

Answer 35

Don't bind in the antigen binding groove Bind on the outside of the antigen presenting cell Many different T cells can bind to a self-MHC that has either a bacterial or viral superantigen that is attached to it

Question 36

Why is high level of MHC polymorphism advantageous?

Answer 36

Most human MHC molecules are expressed at pretty low frequency since there are so many different ones that can bind different antigenic peptide If there was limited expression of MHC, there would be limited binding of those viruses and thus there would be limited response

Question 37

How is serological tissue typing done?

Answer 37

Use HLA molecules since they are expressed on WBCs and you can detect them serologically; have antibodies to almost all of the different alleles that are found Take a donor cell and put it in a dish w/ an antibody to a certain HLA allele → if there is that HLA allele, there will be formation of antigen-antibody complex → add complement → cell membrane lysis if there is antigen-antibody complex → add dye → if there was membrane lysis, the dye is taken up by the cell → if dye was taken up, tells us that this cell expressed that HLA allele

Question 38

MHC typing by PCR hydbridization

Answer 38

Same concept as serological testing, but more sensitive and quicker

Question 39

Mixed lymphocyte reaction

Answer 39

To measure alloreactivity

Question 40

What is the effect of HLA class I and class II matching on allograft survival?

Answer 40

If there are no mismatches at MHC class I and II molecules b/w recipient and donor, have much higher survival rate of graft As you increase the # of mismatches, survival rate decreases