Lecture 11 - TCRs Flashcards
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)
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
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
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
What are ITAMs?
Immunoreceptor Tyrosine-based Activation Motif
• intracellular regions associated w/ TCR
• Tyrosines become phosphorylated → activation
Which part of an Ig does the TCR resemble?
Fab
What are the two ‘types’ of TCRs?
αβ TCRs
γδ TCRs
What are γδ T cells?
These express γδ TCRs
They are different from other T cells
Function unknown
Do not express CD4 or CD8
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
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
Compare TCR specificity at the beginning and end of the immune response
Does not change!
TCRs do not undergo SHM.
Describe the process of somatic rearrangement of the β chain
(very like the heavy chain) • D-J rearrangement • V-DJ rearrangement • transcription • translation
Is segment selection of the β chain random?
No.
If Dβ1 is selected, then Jβ1 will also be selected
Are their CDRs in TCRs?
Yes
3 CDRs, one much more variable than the others (as in Ig)
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
Will simply knowing the Vα and Jα segment sequences tell us everything we need to know about the α chain?
No
There is junctional diversity, due to the N-regions
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
- non-self MHC resembles self-MHC + non-self antigen
- T cell thinks it’s launching a response against non-self antigen
- Response against this allogeneic MHC
→ destruction of graft
Describe an example of molecular mimicry
- A person encounters EBV (Epstein Barr virus) and launches a cellular immune response, and has EBV specific T cells (HLA-B8)
- Person receives a graft
- Most allogeneic cells (w/ allogeneic MHC) won’t be recognised by T cells
- 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
