L13 - Antigen recognition by T cells

Question 1

Define the 2 types of T cell receptors.

Answer 1

1) 95% = conventional T cells with α and β chains

2) 5% = nonconventional T cells: with δ and γ chains

Question 2

Compare the genetic variability and Ag specificity between conventional and unconventional TCRs.

Answer 2

Conventional = Vα, Vβ domains contain 3 hypervariable / complementarity determining regions (CDRs) to determine Ag binding specificity

Unconventional = much lower CDR variability, recognize restricted sets of antigens

Question 3

List the 3 mechanisms for generating TCR diversity?

Answer 3

1) Somatic gene recombination:
i) VDJ gene segments for β chain
ii) VJ gene segments for α chain

2) Junctional diversity: TdT adds N or P nucleotides
3) β chain often uses 3 reading frames in D gene segment **

Question 4

Which has more diversity: BCR or TCR?

Answer 4

TCR

Question 5

List some differences in diversity generation processes of TCR and BCR **

Answer 5

TCR:

• No somatic hypermutation (cannot increase Ag binding affinity after made)
• No switch recombination (TCR sequence fixed in mature T cells)
• No secreted form (only on T cell surface)

Question 6

List some similarities in diversity generation processes of TCR vs BCR?

Answer 6

Both undergo:

• Somatic recombination of DNA
• Junctional diversity
• Transcriptional activation

Question 7

Can T cell responses be transferred from one person to another like antibodies?

Answer 7

No

T cells are MHC restricted: Only able to recognize Ag presented by self MHC

Question 8

Describe the T cell receptor complex and its parts.

Answer 8

• TCR α/β chains = antigen receptor
• CD3: signaling complex = transduce intracellular signals upon antigen binding (function like ITAM in BCR)
• CD4 (monomer) or CD8 (dimer): co-receptor

Question 9

Describe the binding complex between a T cell and an APC?

Answer 9

• TCR complex with CD3 for intracellular signalling/ co-receptor
• TCR binds to peptide antigen presented by MHC-I or II on the APC
• TCR- Ag binding is helped by either CD4 or CD8 co-receptor

Question 10

Define the 2 types of T cells with distinct MHC preference?

Answer 10

1. CD8+ T cells bind α3 domain of MHC class I from all nucleated cells
2. CD4+ T cells bind β2 domain of MHC class II from APCs

Question 11

Compare the MHC class I and II in their structure?

Answer 11

• For MHC class I = α subunit and β2-microglobulin (invariable,never changes) (α1 +α2 +α3 +β2, 8 - 10 amino acids)
• For MHC class II = α subunit and β subunit (α1 + α2 +β1 +β2, 12-30 amino acids)

Question 12

Define MHC restriction?

Answer 12

T cell is restricted to recognize a peptide antigen bound to self MHC molecules only

Question 13

List the processes that generate MHC diversity?

Answer 13

1. Polygeny: both class I and class II has multiple gene loci
2. HLA alleles are co-dominantly expressed
3. High HLA diversity with diverse polymorphism within the population

Question 14

Describe the genetic variation in the loci for MHC-I?

Answer 14

MHC-I = α subunit and β2-microglobulin

• β2-microglobulin = not polymorphic
• 3 polymorphic genes for α chain: HLA-A, HLA-B, HLA-C **
• 3 other genes for non-classical MHC-I: HLA-E, HLA-F, HLA-G (not for conventional T cells, not for peptide presentation)

Question 15

Describe the genetic variation in the loci for MHC-II?

Answer 15

MHC class II = α subunit and β subunit

Multiple genes for both chains:
- HLA-DP, HLA-DQ, HLA-DR ** for peptide antigen presentation

• HLA-DM, HLA-DO = intracellular proteins for loading MHC-II

Question 16

Which chromosome is vital for the genetic variation in MHC?

Answer 16

short arm of chromosome 6

Question 17

Explain how the HLA alleles coding for MHC are expressed?

Answer 17

HLA alleles are co-dominantly expressed

i.e. an individual can express 6 different types of functional MHC-I and 6-8 different types of MHC-II (DRB has multiple genes)

Question 18

Which HLA alleles coding for MHC are highly polymorphic?

Answer 18

HLA class 1: A,B,C genes

HLA Class 2: DRB gene

Question 19

Explain how peptide specificity is achieved in MHC?

Answer 19

Each MHC allele can bind and present distinct sets of peptides

MHC polymorphism*** affects peptide specificity
» determines which peptide antigens are recognized in different individuals

Question 20

MHC-I and II are always present on cell surfaces and await the loading of peptide antigens. T or F?

Answer 20

False

“Empty” MHC molecules are extremely unstable

in normal cells, MHC are bounded with self-peptides

Question 21

Compare the type of peptide antigen presentation pathways between MHC-I and MHC-II? Which antigens are presented?

Answer 21

MHC-I = Cytosolic pathway: present endogenous antigens: intracellular bacteria, virus, self-proteins, proteins in cytosol

MHC-II = Endocytic pathway: present Exogenous antigens: extracellular microbes, protein

Question 22

Describe the process of peptide antigen presentation via MHC-I?

Answer 22

1. Endogenous antigens in cytosol cleaved by proteasomes** into peptide antigens
2. MHC-I made in the ER, stabilized with Chaperone Protein**
3. TAP** (transporter associated with antigen processing) transports peptides into ER: select peptide with right length** to load into MHC-I, Release Chaperone
4. Golgi body translocates MHC-I/peptide complexes to cell surface» present to CD8+ T cells

Question 23

Which cells carry MHC-I? How is it used to alert the immune system of infections?

Answer 23

All nucleated cells (not RBC)

• MHC/self-peptide = not degraded
• MHC/peptide from pathogen = targeted destruction

Question 24

Describe the process of endocytic pathway via MHC-II ?

Answer 24

1. Antigen endocytosis&raquo_space; enclosed in vesicle&raquo_space; combine with lyzosomes to degrade protein
2. MHC-II made and folded in ER, stabilized with chaperone protein&raquo_space; transport via vesicles from Golgi
3. MHC-II vesicles fuse with endolyzosomes&raquo_space; Peptide fragments loaded&raquo_space; MHC-peptide complex translocated to cell surface

> > Present to CD4+ T cells

Question 25

Describe how dendritic cells present exogenous antigens?

Answer 25

Cross-presentation via MHC-I pathway (cytosolic) (usually reserved for intracellular pathogen Ag presentation)
Mechanism unknown

Question 26

Which MHC class do B cells express? How about dendritic cells?

Answer 26

Both I and II

Question 27

Which MHC class do neutrophils and macrophages express?

Answer 27

Neutrophil = only MHC-I

Macrophage = MHC-I and II

Question 28

Which is the only non-haemotapoietic organ that expresses MHC-II highly?

Answer 28

Thymic epithelium

For thymic selection

Question 29

Describe the process of APC presenting Ag to T cells?

Answer 29

1. Capture antigens and migrate to primary or secondary lymphoid organs for T cells interaction
2. Display antigens in a form that can be recognized by specific T cells (i.e. endogenous peptide for MHC-I)
3. Provide co-stimulatory signals for activation of naïve T cells

Question 30

Role of APC in primary and secondary lymphoid organs?

Answer 30

secondary lymphoid organs e.g. spleen or lymph nodes for T cell activation

primary lymphoid organ e.g. thymus for T cell maturation and selection

Question 31

Compare the types of antigens presented by macrophages, dendritic cells and B cells?

Answer 31

Macrophages = Particulate, intracellular and extracellular Ag

Dendritic = Peptide, Viral Ag and Allergens

B cells: Toxins, Viral Ag and Soluble Ag

Question 32

Which APC carry constitutive co-stimulator for T cells?

Answer 32

mature nonphagocytic lymphoid dendritic cells

Question 33

What are alloantigens?

Answer 33

Major or minor histocompatability antigens (MHC or mhc) from donor APCs

> > elicits major immune responses in organ/tissues transplantation

Question 34

What are the 2 pathways for T cells to recognize alloantigens?

Answer 34

Direct vs Indirect pathways

Question 35

Describe the direct pathway for T cells to recognize alloantigens?

Answer 35

Own T cells directly recognize intact allo-MHC on donor APCs

• Low peptide specificity
  »Activate polyclonal T cell responses in recipient

Question 36

Describe the indirect pathway for T cells to recognize alloantigens?

Answer 36

Own APCs endocytose and process donor cell (cytosolic or vesicular pathway)

> > present donor’s allo-MHC peptide on own APC
present to T cells with high peptide specificity