MHC structure/fxn/polymorphism & antigen presentation

Question 1

What is a large cluster of genes that encode specialized host cell glycoproteins?

Answer 1

Major histocompatability complex (MHC)

Question 2

Describe the general function of MHC and how are they related to T cells

Answer 2

some glycoproteins encoded by MHC bind to processed antigens and “present” them on the cell surface

• peptides presented by MHC can be specifically recognized by T cells

Question 3

Describe the MHC class I molecule

Answer 3

MHC I

a chain (HC) encoded by MHC has 3 domains; a1&2 form binding site for peptides ; a3 spans membrane of host cell

B2-microglobulin=>small covalently associated chain not encoded by MHC & folds to form Ig-like domain to associate with a3 domain of MHC class Ia chain

Question 4

T/F Everyone expresses an essentially identical B2-microglobulin

Answer 4

true

Question 5

Describe MHC class II

Answer 5

non-covalent association of 2 polypeptide chains

Both a and B chains are glycosylated transmembrane proteins that have 2 domains

• a2 & B2 are similar to Ig domains
• a1 & B1 form a cleft to bind to peptides

Question 6

Describe the binding groove of each of the MHC molecules

Answer 6

MHC class I molecules are closed on the ends

MHC class II molecules are open on the ends

Question 7

MHC molecules must be able to bind strongly to a diverse array of peptides that is so strong that it will do what?

Answer 7

bound peptide so tight that it co-purifies with them

Question 8

With peptide binding recognizing general features, what is the most important part of the binding?

Answer 8

binding cleft of MHC have pockets where AA residues have a particular structure can anchor peptide

**the sequence of the peptide is not as important as the position of anchor residues **

Question 9

Describe the peptide binding by the MHC class I molecule

Answer 9

• bind to peptides 8-10 AA long and binding groove is closed on each end
• stabilized by contacts bw N-terminal and C-terminal ends of peptide and invariant sites found at ends of binding groove
• peptide lies an elongated conformation along binding groove

Question 10

Describe the binding by MHC class II molecules

Answer 10

• bind to peptides that are at least 13 residues in length & much longer
• ends of the MHC class II binding groove is open ended
• MHC class II molecules accommodate longer peptides

Question 11

What is the degradation of proteins into peptides that can bind to MHC molecules for presentation to T cells?

Answer 11

antigen processing

Question 12

T/F ALL antigens (except peptides) must be processed into pepties before they can presented via MHC molecules

Answer 12

true

Question 13

***Where does antigen processing take place within cells?***

Answer 13

1. cytosol
2. endocytic vesicles

Question 14

Describe the antigen processing in the cytosol

Answer 14

1. antigens derived from pathogens that replicate in cytoplasm of cells are degraded into peptide fragments by a proteosome

Question 15

What is a large cylindrical complexes whose fxn is to recycle cytosolic proteins which they enzymatically chop them into small pieces?

Answer 15

proteosome

Question 16

What happens to the peptides that are produced by the proteosome? What complex is needed?

Answer 16

actively transported to the lumen of the ER where they bind to MHC class I molecule

the TAP transporter complex is needed

Question 17

Describe the TAP transporter complex

Answer 17

TAP transporter complex is an ATP-dependent peptide transporter complex consisting of a TAP1, 2 protein

Question 18

Peptides from foreign proteins bind to what MHC?

Answer 18

MHC class I molecules

Question 19

Why are self peptides usually not recognized by patroling CD8 effector cells?

Answer 19

most self-reactive T cells are clonally deleted during the negative selection process in the thymus

only non-self peptides should be recognized by CTLs

Question 20

Where antigens that are phagocytosed confined to? What happens there?

Answer 20

endocytic vesicles

antigen is degraded by endosomal or lysosomal proteases into peptide fragments

Question 21

antigens that are confined to endosomal compartment are not available for what?

Answer 21

proteosome for processing

Question 22

Where are peptide fragments within endocytic vesicles bind to what and transported where?

Answer 22

bind to MHC class II molecules

MHC:peptide complex is transported to cell surface

Question 23

Peptides generated within endosomal compartments are recognized by what?

Answer 23

recognized by CD4 T cells since they bind to MHC class II molecules

Question 24

What associates with newly synthesized MHC class II molecules and prevents peptides that are in the ER from bindin in the peptide-binding groove of these molecules?

What happens with the new MHC class II: invariant chain complex?

Answer 24

invariant chain

transported to acidified vesicles where the invariant chain is degraded leaving only the clip peptide attached in the binding groove

Question 25

A clip protein is associated with what?

Answer 25

Class II-associated invariant chain peptide

Question 26

Upon interaction with the vesicle membrane protein HLA-DM, the MHC class II molecule does what?

Answer 26

releases clip peptide and then available for binding to peptides within the vesicle

Question 27

What happens if a peptide does not bind in the clef of the MHC class II molecule quickly? What if it does bind?

Answer 27

the class II molecule will be degraded complex is stabilized and exported to surface of the cell for antigen presentation

Question 28

Name where intracellular pathogens in ANY cell are processed, bound and presented

Answer 28

* processed by proteosomes in cytosol of infected cell * peptides bind to MHC I and MHC:peptide complex are transported to surface of cell * peptides are presented to antigen-specific CD8 T cells

Question 29

Extracellular pathogens (bacteria) are endocytosed by what?

Answer 29

macrophages, dendritic cells, or B cells

Question 30

Name extracellular pathogens are processed, bound, and presented

Answer 30

* endocytosed antigen processed w/in endocytic vesicles * bind to MHC II molecules and MHC:peptide complex is displayed on surface of cell * presented to antigen-specific CD4 T cells

Question 31

Extracellular pathogen, pathogen-derived antigen or toxin binds to what?

Answer 31

binds to B cell receptor on an antigen-specific B cell

Question 32

Name where the extracellular pathogen, pathogen-derived pathogen or toxin is processed, bound, presented

Answer 32

* endocytosed and processed by the B cell * bound to MHC II molecules and presented on surface of B cell * presented to antigen-specific CD4 T cells

Question 33

T/F MHC I and II are expressed differentially on cells

Answer 33

true

Question 34

MHC class I present peptides derived from what? where? to what?

Answer 34

* derived from pathogens * in the cytosol * to either naive or effector CD8 T cells

Question 35

CD8 T cells are programmed to kill any cell that presents what?

Answer 35

their cognate antigen via MHC class I molecules

Question 36

MHC class II molecules present peptides produced by what? to what?

Answer 36

* produced by processing in endocytic vesicles * to either naive or effector CD4 T cells (T helper)

Question 37

Where are MHC class II molecules found?

Answer 37

on antigen presenting cells

Question 38

CD4 T cells are activated by the antigen presenting cells (APC). What is the primary role of these?

Answer 38

to activate other cells of the immune system

Question 39

Other than APCs, where else are MHC II molecules present on? Why is this important?

Answer 39

* present on thymic cortical epithelial cells * important in positive selection of MHC-binding thymocytes durin the thymic maturation process

Question 40

What does the MHC gene complex encode?

Answer 40

* TAP 1, TAP 2 * proteosomes * variety of cytokines * several complement proteins

Question 41

What are teh most polymorphic genes in the mammalian genome?

Answer 41

MHC class I and II

Question 42

\*\*\*Describe the 2 properties of MHC that make it difficult for pathogens to evade immune responses in this way\*\*\*

Answer 42

1. MHC is polygenic but MHC I and II found on chromosome 6 2. MHC class I and II genes are highly polymorphic (multiple alleles for each isoform)

Question 43

What isoforms are found on MHC class I? Where are they expressed?

Answer 43

HLA-A, HLA-B, HLA-C all expressed on most cells

Question 44

What are the isoforms of MHC class II? where are they expressed?

Answer 44

HLA-DP, HLA-DQ, HLA-DR all expressed by most B cells, APCs, thymic epithelial cells

Question 45

T/F MHC class I and II molecules experience NO rearrangement or somatic alterations occur

Answer 45

True

Question 46

Where does the diversity of MHC expression result from?

Answer 46

polygeny(for each individual) and polymorphism (w/in population)

Question 47

What is a naturally occuring variant of a particular gene?

Answer 47

allele

Question 48

What is a different form of a protein that is encoded by the alleles of a gene or by different but closely related genes?

Answer 48

isoform

Question 49

For a linked set of polymorphic genes, the set of alleles carried on a single chromosome 6 is what?

Answer 49

haplotype

Question 50

What are the 6 isoforms of MHC class I? Which are highly polymorphic and what is their function?

Answer 50

* Highly polymorphic: HLA-A, HLA-B, HLA-C =\> present peptide antigens to T cells HLA-E, HLA-F, HLA-G

Question 51

Which MHC I isoforms are oligomorphic and form ligands for NK cell receptors? What immune system is involved?

Answer 51

HLA-E and HLA-G involved in innate immune responses

Question 52

What isoform is monomorphic and remains intracellular with unknown function?

Answer 52

HLA-F

Question 53

What are the 5 isoforms of MHC II? Which are highly polymorphic? What do they present to?

Answer 53

1. **HLA-DR** 2. **HLA-DQ** 3. **HLA-DR** 4. HLA-DM 5. HLA-DO **highly polymorphic cells present them to CD4 T cells**

Question 54

Which isoforms of MHC II are oligomorphic and have regulatory roles in peptide loading onto HLA-DP, HLA-DQ, and HLA-DR?

Answer 54

HLA-DM and HLA-DO

Question 55

T/F MHC II molecules are heterodimeric What are they composed of?

Answer 55

true composed of an alpha chain and a beta chain

Question 56

Why does a fully heterozygous person express 2 haplotypes of each MHC genes?

Answer 56

each individual expresses both alleles of each HLA gene

Question 57

What is the minimum number of HLA class I isoforms expressed by an individual? maximum?

Answer 57

3 if homozygous at each loci 6 if heterozygous at each loci

Question 58

What is the minimum number of HLA class II isoforms? maximum? Why is this more complicated?

Answer 58

9 with 3 B chains paired w/ 3 different distinct a chains 48 each a and B chain is heterozygous and HLA-DR B chain is inherited on each chromosome =\> 8 distinct B chains w/ potential to pair w/ 6 a chains

Question 59

How does the polymorphism affect the peptide binding ability of MHC molecules?

Answer 59

different forms of MHC I and II expressed by different individuals can be highly divergent but still function properly * ex: differences bw differnt forms of HLA-A are concentrated in regions of MHC molecule taht binds peptide or binds to TCR molecule =\> alterations in regions of MHC gives rise to differences in peptide binding characteristics of different form of HLA-A =\> true for each of MHC I and II

Question 60

Describe transplant rejection

Answer 60

transplanted tissues or organs from donors bearing MHC molecules that differ from those of recipient are reliably rejected

Question 61

What is the rejection of a graft primarily the result of? Describe this action

Answer 61

result of a potent T cell mediated immune response * large % of T cells in recipient react specifically w/ particular **allogenic (non-self)** MHC molecules

Question 62

Describe graft vs host disease

Answer 62

prior to bone marrow transplant-recipient immune system is destroyed following transplantation, mature T cells from the donor bone marrow attacks recipients tissues

Question 63

A transplant bw genetically identical individuals is called what?

Answer 63

syngeneic transplant or isograft

Question 64

A transplant bw genetically differnet ppl is called what?

Answer 64

allogeneic transplant or an allograft

Question 65

A transplant from one species into a different species is what?

Answer 65

xenograph

Question 66

A transplant of tissue from one area of an individual's body to a different area of the same individual is called what?

Answer 66

autograft

Question 67

T/F T cells ONLY recognize peptides bound to MHC molecules

Answer 67

true

Question 68

How is peptide binding of MHC I stabilized?

Answer 68

* contacts between the aminoterminal and carboxyterminal ends of the peptide * invariant sites found at the ends of the binding grooves