Lecture 11 - TCRs

Question 1

What are the main properties of the TCR?

Answer 1

• Ig-like molecule: (has Ig domains in it)
• recognises MHC + antigen
• only one TCR specific for each cell
• weak affinity between TCR and Ag
• Engagement trigger proliferation & induction of effector function (analogous to clonal expansion in B cells)

Question 2

Which effector function is gained through clonal selection of T cells by APC’s?

Answer 2

CD8+ T cells: Ability to kill

CD4+ T cells: expression of CD40L, ability to stimulate B cells

Question 3

Describe the structure of the TCR

Answer 3

• two chains: α and β
• per chain: C and V domains
• 4 extracellular Ig domains
• intrachain disulphide bonds
• disulphide bond holding together α and β chains

Question 4

Describe the TCR signalling complex, and how TCRs signal

Answer 4

• TCR with charged residues
• Signalling molecules: CD3, containing ITAMs

Charged residues associate with signalling molecules: CD3

Question 5

What are ITAMs?

Answer 5

Immunoreceptor Tyrosine-based Activation Motif
• intracellular regions associated w/ TCR
• Tyrosines become phosphorylated → activation

Question 6

Which part of an Ig does the TCR resemble?

Answer 6

Fab

Question 7

What are the two ‘types’ of TCRs?

Answer 7

αβ TCRs

γδ TCRs

Question 8

What are γδ T cells?

Answer 8

These express γδ TCRs
They are different from other T cells
Function unknown
Do not express CD4 or CD8

Question 9

The heavy chain and the … chain of TCR are structurally similar.
Why?

Answer 9

β chain
Have V, D, J and C domains

Furthermore,
α and Light chains are structurally similar:
V, J and C domains

Question 10

How do TCRs get their diversity?

Answer 10

Same processes as Igs:
• somatic rearrangement
• 12/23 rule
• Recombinase enzyme complex used (RAGs)

NB TCRs do not undergo somatic hypermutation

Question 11

Compare TCR specificity at the beginning and end of the immune response

Answer 11

Does not change!

TCRs do not undergo SHM.

Question 12

Describe the process of somatic rearrangement of the β chain

Answer 12

(very like the heavy chain)
 • D-J rearrangement
 • V-DJ rearrangement
 • transcription
 • translation

Question 13

Is segment selection of the β chain random?

Answer 13

No.

If Dβ1 is selected, then Jβ1 will also be selected

Question 14

Are their CDRs in TCRs?

Answer 14

Yes

3 CDRs, one much more variable than the others (as in Ig)

Question 15

Describe the location of CDRs in TCRs

Answer 15

At the tip of the Vα and Vβ segments

Easily accessible for interaction w/ the peptide in MHC

Question 16

Will simply knowing the Vα and Jα segment sequences tell us everything we need to know about the α chain?

Answer 16

No

There is junctional diversity, due to the N-regions

Question 17

What do superantigens do?
What are some examples?
Describe what they bind to

Answer 17

Stimulate great numbers of T cells
e.g.
• TSST (Toxic shock syndrome toxin)
• Staphylococcal enterotoxin

Bind to:
• MHC II
• V segment of the β chain

NB will not bind to MHC I

Question 18

Compare MHC-bound peptides and Superantigens, in terms of complementarity

Answer 18

MHC-bound:
• these peptides select TCRs based on the entire rearranged TCR sequence of V,D and J
• only a tiny proportion of the TCRs will have the appropriate sequence

Superantigens:
• Ag selects TCRs based only on the Vβ sequence
• Regardless of D or J
• 1-10% of TCRs will have the correct Vβ
→ a huge number of T cells will be selected by a given super antigen

Question 19

Describe the configuration of the TCR genes in the various cells in the body

Answer 19

In T cells: have undergone somatic rearrangement

In all other cells in the body: in germ line configuration

Question 20

What is allelic exclusion and when is it seen?

Answer 20

Allelic exclusion: once successful rearrangement of the segments has occurred, no further rearrangement can take place.
→ ensures only one TCR specificity per T cell

This occurs in:
• Ig gene rearrangement
• TCR gene rearrangement

Question 21

Describe the lay out of the α chain locus

Answer 21

Vα(1-70)
Jα(1-50)
Cα

Question 22

Describe the layout of the β chain locus

Answer 22

Vβ (1-50)
Dβ (1-2)
Jβ (1.1 - 1.6 & 2.1-2.6)
Cβ (1-2)

Question 23

Which CDR of the TCR makes the dominant connection with peptide in MHC?
Describe this association

Answer 23

CDR3 (of both the α & β chains)

• The TCR always sits diagonal, relative to MHC
• There is no hard and fast rule as to the configuration, only trends

• the regions that aren’t making contacts with the peptide are important, because they are setting up the configuration so that other residues can make the contacts

Question 24

How many V segments in the α & β chains?

Answer 24

α: 70

β: 50

Question 25

How many D segments in the α & β chains?

Answer 25

α: 0

β: 2

Question 26

How many J segments in the α & β chains?

Answer 26

α: 50

β: 12

Question 27

Is the α chain more like the heavy or the light chain?

Answer 27

α is more like the light chain

Question 28

How much of TCR diversity is thanks to the junctional diversity?

Answer 28

Over 2/3rds of diversity

10^11

Question 29

Describe generally the ‘type’ of MHC and peptide that TCR are selected to recognise

Answer 29

• self MHC (to a certain extent)

* foreign peptide

Question 30

When is allogeneic MHC?

Why is it important?

Answer 30

Foreign MHC
non-self MHC

Allogeneic MHC is the main barrier to successful organ transplant, because allogeneic responses are quite strong

Question 31

Why is there variability in survival of grafts?

Answer 31

Successful grafting depends on HLA matching.

The more mismatches, the worse the outcome of the graft

Question 32

What happens if (during thymic development) a TCR recognises self-MHC?

Answer 32

Recognition: positive selection

Too ‘tight’ recognition: negative selection → death of developing T cell

Question 33

Is self-MHC recognition by TCR sufficient for activation of the T cell?

Answer 33

No

• antigenic peptide must be bound to the MHC for activation

Question 34

Describe allorecognition

Answer 34

• In a graft there will by allogeneic MHC (non-self MHC) with self antigen in the binding groove

1. non-self MHC resembles self-MHC + non-self antigen
2. T cell thinks it’s launching a response against non-self antigen
3. Response against this allogeneic MHC
   → destruction of graft

Question 35

Describe an example of molecular mimicry

Answer 35

1. A person encounters EBV (Epstein Barr virus) and launches a cellular immune response, and has EBV specific T cells (HLA-B8)
2. Person receives a graft
3. Most allogeneic cells (w/ allogeneic MHC) won’t be recognised by T cells
4. Some allogeneic MHC (HLA-B44) will be recognised by the EBV-sepcific T cell, and will thus be killed by the T cell

Question 36

Where are the disulphide bonds in TCRs?

Answer 36

• within the 4 domains

* between the α and β chains

Question 37

Which types of MHC will super antigens bind?

Answer 37

Only MHC II, not MHC I

Question 38

Why is the ‘4th hypervariable loop’ important?

Answer 38

Superantigens bind to this region, i.e. Vβ segment

Question 39

Describe the affinity between TCR and Ag (presented on MHC)

Answer 39

Weak affinity

Such that the Ag could be washed off

Question 40

If a self-MHC molecule interacts with a TCR with moderate affinity, but does not elicit an immune response, how is the immune response elicited?

Answer 40

Also need foreign-peptide presented in binding cleft

These contacts result in the activation of the T cell