Lecture 11 - TCRs Flashcards by Eleanor Nicklason

What are the main properties of the TCR?

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)

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

CD8+ T cells: Ability to kill

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

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Describe the structure of the TCR

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

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Describe the TCR signalling complex, and how TCRs signal

TCR with charged residues
Signalling molecules: CD3, containing ITAMs

Charged residues associate with signalling molecules: CD3

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What are ITAMs?

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

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Which part of an Ig does the TCR resemble?

Fab

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What are the two ‘types’ of TCRs?

αβ TCRs

γδ TCRs

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What are γδ T cells?

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

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

β chain
Have V, D, J and C domains

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

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How do TCRs get their diversity?

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

NB TCRs do not undergo somatic hypermutation

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

Does not change!

TCRs do not undergo SHM.

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Describe the process of somatic rearrangement of the β chain

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

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Is segment selection of the β chain random?

No.

If Dβ1 is selected, then Jβ1 will also be selected

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Are their CDRs in TCRs?

Yes

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

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Describe the location of CDRs in TCRs

At the tip of the Vα and Vβ segments

Easily accessible for interaction w/ the peptide in MHC

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

There is junctional diversity, due to the N-regions

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

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

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

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

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

In T cells: have undergone somatic rearrangement

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

What is allelic exclusion and when is it seen?

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

Describe the lay out of the α chain locus

Vα(1-70)
Jα(1-50)
Cα

Describe the layout of the β chain locus

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

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

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

How many V segments in the α & β chains?

α: 70

β: 50

How many D segments in the α & β chains?

α: 0 | β: 2

How many J segments in the α & β chains?

α: 50 | β: 12

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

α is more like the light chain

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

Over 2/3rds of diversity | 10^11

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

* self MHC (to a certain extent) | * foreign peptide

When is allogeneic MHC? | Why is it important?

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

Why is there variability in survival of grafts?

Successful grafting depends on HLA matching. | The more mismatches, the worse the outcome of the graft

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

Recognition: positive selection Too 'tight' recognition: negative selection → death of developing T cell

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

No | • antigenic peptide must be bound to the MHC for activation

Describe allorecognition

• 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

Describe an example of molecular mimicry

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

Where are the disulphide bonds in TCRs?

* within the 4 domains | * between the α and β chains

Which types of MHC will super antigens bind?

Only MHC II, not MHC I

Why is the '4th hypervariable loop' important?

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

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

Weak affinity | Such that the Ag could be washed off

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?

Also need foreign-peptide presented in binding cleft | These contacts result in the activation of the T cell