MHC and antigen-presentation

Question 1

(T/F) Because it is impossible for a few T cells to constantly patrol all possible tissues where antigens can be found, APCs capture antigens and display them to T cells in the lymphoid organs.

Answer 1

True!

Question 2

Most T lymphocytes can recognize only:

while B cells can recognize:

Answer 2

Short peptides

Peptides, proteins, nucleic acids, carbohydrates, lipids, and small chemicals

Question 3

What are major histocompatibility complex molecules (MHC)?

Answer 3

MHC molecules display antigens for recognition by CD4+ and CD8+ T cells.

Question 4

(T/F) Different T cells respond to microbial antigens in distinct cellular compartments, such as extracellular and intracellular locations.

Answer 4

True!

Question 5

How is defense against viruses in the circulation different from the defense against viruses in tissue cells?

Answer 5

Defense against viruses in the circulation is mediated by antibodies with the help of CD4+ helper T cells, while the eradication of viruses in tissue cells (inaccessible to antibodies) requires CD8+ cytotoxic T lymphocytes (CTLs) to kill the infected cells.

Question 6

Differentiate CD4 helper T cell vs CD8 cytotoxic T cell.

1) In response to

2) What presents antigen

3) What MHC pathway is used

Answer 6

CD4 helper T cell
1) EXTRACELLULAR PATHOGEN
2) APCs (dendritic cells, macrophages, and B cells)
3) CLASS II

CD8 cytotoxic T cell
1) INTRACELLULAR pathogen
2) ANY NUCLEATED CELL
3) CLASS I

Question 7

(T/F) T cell response requires the presentation of the antigen to T cells by other cells.

Answer 7

True!

Question 8

1) Which type of antigen-presenting cells (APCs) are most effective at activating NAIVE T cells and initiating T cell responses?

2) What are the primary functions of macrophages and B lymphocytes in the immune response?

3) How do effector CD4 T cells contribute to pathogen destruction and antibody production?

Answer 8

1) Dendritic cells.

2) Macrophages and B lymphocytes primarily function to support previously activated (effector) CD4+ helper T cells.

3) Effector CD4 T cells, upon recognizing antigen, produce cytokines that can activate macrophages to destroy pathogens and help B cells in the production of antibodies against antigens.

Question 9

What are the four properties of dendritic cells that make them the most efficient APCs for initiating primary T cell responses?

Answer 9

Dendritic cells (DCs) are efficient APCs because they:

1) Are strategically located at sites of microbial entry and in susceptible tissues.

2) Express receptors for capturing and responding to microbes.

3) Migrate from tissues and epithelia via lymphatics to T cell zones in lymph nodes, where naive T lymphocytes are found.

4) When mature, express high levels of peptide-MHC complexes, costimulators, and cytokines, all necessary for activating naive T lymphocytes.

Question 10

1) How were dendritic cells initially identified, and what distinguishes their characteristic morphology?

2) What are LANGERHANS cells?

Answer 10

1) Dendritic cells were identified by their morphology, featuring spine-like projections resembling dendrites of neurons. They stimulate strong T cell responses.

2) Langerhans cells are dendritic cells that populate the EPIDERMIS; they present antigens encountered in the skin.

Question 11

1) How do resident dendritic cells in epithelia and tissues capture protein antigens, and what do they do with these antigens?

2) What activates dendritic cells and transforms them into potent antigen-presenting cells (APCs), and where do they transport the captured antigens?

Answer 11

1) Resident dendritic cells in epithelia and tissues capture protein antigens using membrane receptors such as C-type lectins. They then process these antigens into peptides capable of binding to MHC molecules.

2) Dendritic cells are activated by microbial products, which causes them to mature into potent APCs. These activated dendritic cells transport the captured antigens to draining lymph nodes.

Question 12

Differ tissue resident dendritic cells to activated dendritic cells.

Answer 12

Tissue resident dendritic cell:
- principal function is antigen capture
- high expression of Fc and mannose receptors
- low expression of molecules involved in T cell activation
- short half life

Activated dendritic cell:
- principal function is to present antigen to T cells
- low expression of Fc and mannose receptors
- high expression of molecules involved in T cell activation
- longer half life

Question 13

1) What is the primary role of the major histocompatibility locus, a single genetic region within the mouse MHC?

2) What do the human MHC and the mouse MHC have in common in terms of basic structure and significance?

Human MHC: HLA (Human Leukocyte Antigen)
Mouse HMC: H-2 complex

Answer 13

1) The major histocompatibility locus is primarily responsible for the rapid rejection of tissue grafts.

2) The human MHC plays a major role in determining graft acceptance or rejection, similar to the mouse MHC. Both have proteins that exhibit similar basic structures.

Question 14

Match the four different types of graft to their definitions:

1) Autologous graft
2) Syngeneic graft
3) Allogeneic graft (allograft)
4) Xenogeneic graft (xenograft)

Answer 14

1) Autologous graft: a graft transplanted from one individual to the same individual

2) Syngeneic graft: a graft transplanted between two genetically identical individuals

3) Allogeneic graft (allograft): a graft transplanted between different individuals of the same species

4) Xenogeneic graft: a graft transplanted between individuals of different species

Question 15

Which grafts are most likely to be rejected?

Answer 15

Allograft - most likely rejected

Xenograft - always rejected

MHC is responsible for graft rejection due to MHC restriction!

TCRs (on recipient) can only recognize self MHC molecules. Tissue graft (from donor) have non-self MHC molecules, which can not be recognized by TCRs. Thus, the immune system attempts to reject the graft.

Question 16

(T/F) Memory T cells can induce a fast and enhanced graft rejection as opposed to naive T cells.

Answer 16

True!

Graft rejection would occur faster if it was the second time something was being grafted from the same donor.

Question 17

Effector T cells only respond to peptide present on the ___-MHC molecules.

Answer 17

Self

Question 18

Briefly describe the MHC restriction phenomenon.

Answer 18

T cell antigen recognition is restricted by the MHC molecule a T cell sees.

For example, if a mouse is infected with a virus, CD8+ T cells specific for the virus develop only when the infected cells express an antigenic peptide on the context of a SELF (host’s own) MHC molecule.

If the antigenic peptide of virus is expressed in NON-SELF MHC molecules, CD8+ T cells for that virus do not develop in that mouse.

The recognition of antigens by CD8+ T cells is restricted by self class I MHC alleles while it is self class II MHC alleles for CD4+ T cells.

Question 19

The MHC locus contains two types of _________ MCH genes: class I and class II.

These encode two groups of structurally ________ but _______ proteins.

The locus also contains other __________ genes whose products are involved in antigen presentation.

Answer 19

polymorphic

distinct; homologous

non-polymorphic

Question 20

What are the most polymorphic genes present in any mammalian genome?

Answer 20

Class I and class II MHC genes

Question 21

Define polymorphism

Answer 21

The existence of two or more alternative forms, or variants (called alleles), of a gene that are present at stable frequencies in a population.

Class I and class II MHC genes are highly polymorphic, with numerous alleles.

Question 22

1) The polymorphic residues of MHC molecules are responsible for what?

2) Why may have MHC polymorphism evolved?

Answer 22

1) The polymorphic residues of MHC molecules determine the specificity of peptide binding and T cell antigen recognition.

2) Ensures that individuals will be able to deal with diversity of microbes and populations can be protected from devastating loss of life form emerging infections.

Question 23

(T/F) Complement protein and cytokine genes are present in the middle of class II and class I MHC locus. Proteasome genes are present within the class II locus.

Answer 23

True!

Question 24

________ and _______ both contribute to the diversity of MHC molecules expressed by an inidvidual.

Answer 24

polymorphism; polygeny

*polygenic: made up of multiple genes.
*polymorphism: presence of different alleles of a gene.

Question 25

The expression of MHC molecules is increased by cytokines produced during innate and adaptive immune responses.

1) Class I expression is increased by:

2) Class II expression is increased by:

Answer 25

1) type I interferons (IFN-alpha and IFN-beta)

2) IFN-g

Question 26

Each MHC molecule consists of an __________ cleft, followed by _________-like domains and _______ and _______ domains.

Answer 26

extracellular peptide-binding; immunoglobin (ig); transmembrane; cytoplasmic

Question 27

1) Where are the polymorphic amino acid residues of MHC molecules located?

2) What is the function of the non-polymorphic Ig-like domains?

Answer 27

1) located in and adjacent to peptide-binding cleft

2) contain binding sites for the T cell molecules CD4 and CD8

Question 28

What are the components of class I MHC molecules, and how are they structured?

Answer 28

Class I MHC molecules consist of two non-covalently linked polypeptide chains: an MHC-encoded α chain and a non-MHC-encoded β2-microglobulin.

The α1 and α2 segments (90 residues long) of the α chain form a platform of an 8-stranded, antiparallel b-pleated sheet supporting two parallel strands of alpha helix, forming the PEPTIDE-BINDING CLEFT.

Question 29

What size of peptides can the peptide-binding cleft in class I MHC molecules accommodate?

Answer 29

The peptide-binding cleft of class I MHC molecules accommodates peptides of 8 to 11 amino acids in a flexible, extended conformation.

The ends of the class I peptide-binding cleft are closed so that larger peptides can not be accomodated.

Question 30

1) How is a fully assembled class I MHC molecule composed, and what is necessary for stable expression on cell surfaces?

2) Why do most individuals express six different class I molecules on their cells?

Answer 30

1) A fully assembled class I MHC molecule is a TRIMER composed of an α chain, β2-microglobulin, and a bound peptide. Stable expression on cell surfaces requires all three components.

2) Most individuals are heterozygous for MHC genes, resulting in the expression of six different class I MHC molecules on every cell, containing α chains encoded by the two inherited alleles of the HLA-A, B, and C genes.

Question 31

What are the components of class II MHC molecules, and how are they structured?

Answer 31

MHC class II molecules consist of two non-covalently associated peptide chains, an α and a β chain. Both are POLYMORPHIC and present in the MHC locus.

The amino terminal α1 and β1 form the PEPTIDE-BINDING CLEFT, similar to class I.

Question 32

What size of peptides can the peptide-binding cleft in class II MHC molecules accommodate?

Answer 32

Since the ends of the peptide-binding cleft are open, the peptides of up to 30 residues can be accommodated.

Usually 13-18 residues.

Question 33

1) How is a fully assembled class II MHC molecule composed, and what is necessary for stable expression on cell surfaces?

2) How many class II MHC alleles can an individual inherit?

Answer 33

1) The fully assembled class II molecule is a TRIMER consisting of one alpha and one beta chain, and a bound antigen peptide. Stable expression on cell surfaces requires the presence of all 3.

3) six-eight; three or four from each parent (one set of DP, DQ and one or two of DR).

Question 34

Fill in the blanks:

1) The polymorphic residues of class I molecules are confined to the ___ and ___ domains, where they contribute to variations among different class I alleles in ______ _____ and __ cell recognition

2) The polymorphic residues of class II molecules are located in the ____ and ____ segments, in and around the peptide-binding cleft, as in class I molecules. In human class II molecules, most of the polymorphism is in the ___ chain.

Answer 34

1) α1 and α2; peptide binding; T

2) α1 and β1; β

Question 35

MHC molecules show a _____ specificity for peptide binding, in contrast to the ____ specificity of antigen recognition by the T cell receptors.

Each class I or class II MHC molecule has a single peptide-binding cleft that binds ___ peptide, but each MHC molecule can bind _____ different peptides.

The association of peptides and MHC molecules is a _____ interaction with a very _____ off-rate.

Answer 35

broad; fine

one; many

saturable; slow

Question 36

1) How many peptide-MHC complexes are typically capable of activating specific T lymphocytes?

2) Do MHC molecules distinguish between foreign peptides and self peptides, and how are T cells specific for self peptides handled within the immune system?

Answer 36

1) Very small numbers; as few as 100 complexes of a particular peptide with a class II MHC molecule on the surface of an APC can initiate a specific T cell response (less than 0.1%).

2) MHC molecules of an individual do not distinguish between foreign and self peptides. However, T cells specific for self peptides are typically eliminated or inactivated in the thymus during T cell development to prevent autoimmunity.

Question 37

1) The binding of peptides to MHC molecules is a _________ interaction mediated by residues both in the ______ and in the _____ of the MHC molecules.

2) The antigen receptors of T cells recognize both the
_______ peptide and the _____ molecules, with the
peptide being responsible for the _____ specificity of antigen recognition and the MHC residues accounting for the MHC ______ of the T cells.

Answer 37

1) non-covalent; peptides; cleft

2) antigenic; MHC; fine; restriction

Question 38

All peptides that bind to class I molecules contain a __________ anchor. These are often ________ residues.

Another anchor residue found is often at the 2nd, 2nd and 3rd, positions of the _______ -terminal end of the peptide.

Answer 38

carboxyl-terminal (position 9); hydrophobic

amino

*knowledge of those key positions and the chemical restrictions for amino acids at these positions may allow to generate more powerful vaccines targeted at eliciting protective immunity to particular pathogens

Question 39

(T/F) In general, any peptide of the correct length that contains the different or chemically different anchor residues will bind to the same class I MHC molecule.

Answer 39

False!

Any peptide of the correct length that contains the SAME or chemically SIMILAR anchor residues will bind to the same class I MHC molecule.

Question 40

What is antigen processing?

Answer 40

MHC molecules can bind only peptides but most antigens are large proteins.

Antigen processing breaks these proteins into peptides whether in the cytosol or internalized from the extracellular environments, into peptides that can be loaded onto MHC molecules for T cell presentation.

Question 41

1) What is required for the stable assembly and surface expression of class I and class II molecules?

2) How does the origin of protein antigens, whether they are present in the cytosol or internalized from the extracellular environment, influence the type of peptides generated and the T cells they are recognized by?

Answer 41

1) PEPTIDE ASSOCIATION is required for the stable assembly and surface expression of class I and class II molecules.

2) Protein antigens present in the cytosol, typically synthesized within the cell, generate class I-associated peptides recognized by CD8+ T cells.

Antigens internalized from the extracellular environment into the vesicles of APCs generate peptides displayed by class II MHC molecules and recognized by CD4+ T cells.

Question 42

Briefly describe the processing and presentation of cytosolic proteins for the class I MHC pathway.

Answer 42

Class I MHC associated peptides are produced by proteolytic degradation of cytosolic proteins (synthesized within cells) in PROTEASOMES (ubiquintilation), and these are translocated to the ER by the transporter associated with antigen processing (TAP), where they bind to newly synthesized class I molecules through TAPASIN.

Class I MHC molecules with bound peptides are structurally stable and are expressed on the cell surface.

Question 43

What is ERAP?

Answer 43

ER associated peptidase

It further adjusts the size of the peptide in the ER of class I MHC molecules.

Question 44

Most class II MHC associated proteins are derived from protein antigens that are digested in _______ and _____ in ______.

What happens to these internalized proteins?

Answer 44

Endosomes; lysosomes; APCs

Internalized proteins are degraded enzymatically in late endosomes and lysosomes to generate peptides that are able to bind to the peptide-binding cleft of class II MHC molecules

Question 45

Briefly answer the following questions regarding processing and presenting of vesicular proteins for class II MHC pathway:

1) Where are Class II MHC molecules synthesized and where are they transported?

2) What is the invariant chain (li)? What happens to it?

3) What is CLIP?

Answer 45

1) Class II molecules are synthesized in the ER and transported to ENDOSOMES.

2) Invariant chain, an associated protein, occupies the peptide-binding clefts of the class II MHC molecules to help them transport to the endosomes.

The vesicles containing the class II Molecules and invariant chain FUSES with a LYSOSOME that contains the antigenic peptides. Within the lysosomal vesicle, the invariant chain is degraded.

3) Invariant chain is degraded to Class II-associated invariant chain peptide (CLIP)!

Question 46

What happens after the formation of CLIP in class II MHC pathway?

Answer 46

CLIP dissociates from class II MHC molecules by the combined action of PROTEOLYTIC ENZYMES and the HLA-DM molecule.

This allows antigenic peptides to bind to the now available peptide-binding clefts of the class II molecules.

Question 47

How are class II MHC molecules stabilized?

What happens after stabilization?

Answer 47

They are stabIlized by the BOUND PEPTIDES.

The stable peptide-complexes are delivered to the surface of APCs, where they are displayed for recognition by CD4+ T cells.

Question 48

Briefly answer these for both class I and class II MHC pathway:

1) Source of protein antigens

2) Enzymes that generate the peptides

3) Site of peptide loading of MHC

4) Molecules involved in peptide transport and MHC loading

Answer 48

CLASS I MHC PATHWAY

1) Source of protein antigens: cytosolic

2) Enzymes that generate the peptides: cytosolic proteasome

3) Site of peptide loading of MHC: ER

4) Molecules involved in peptide transport and MHC loading: chaperones, TAP

CLASS II MHC PATHWAY
1) Source of protein antigens: endosomal/lysosomal proteins (internalized)

2) Enzymes that generate the peptides: endosomal/lysosomal proteases

3) Site of peptide loading of MHC: specialized vesicular compartment

4) Molecules involved in peptide transport and MHC loading: chaperones, invariant chain

Question 49

(T/F) Dendritic cells, macrophages, B cells only express class II molecules.

Answer 49

False!

Since these are nucleated cells, they express class I molecules as well. However, these are the only cells that express class II molecules!

Question 50

What is cross presentation?

Answer 50

Only dendritic cells are capable of activating all NAIVE T cells.
They have to become infected by the cytosolic pathogen for antigen presentation. But some viruses, such as HIV, do not infect dendritic cells.

Some dendritic cells capture and ingest virus infected cells or tumour cells and present the viral or tumour antigens to naive CD8+ T lymphocytes on their class I MHC molecules - cross presentation!

This ensures that cytotoxic T cells against such viruses can always be generated!

Question 51

The epitopes of complex proteins that elicit the strongest T cell responses are the peptides that are generated by ______ in ______ and bind most ______ to MHC molecules.

The majority of the responding T cells are specific for only one or a few linear amino acids sequences of the antigen called the:

Answer 51

proteolysis; APCs; avidly

immunodominant epitopes or determinants