Lecture 12: T Cell Receptor Genetics, Structure, Functional Recognition and Signalling

Question 1

What are important properties of the TCR?

Answer 1

recognises MHC:peptide complex
Ig-like molecule expressed on T cells
only one TCR specific per T cell

Question 2

What is the structure of a TCR?

Answer 2

consists of Ig-like domains which are about 100aa long

consists of an ɑ- and β-chain

Question 3

What do most T cells recognise the peptide/MHC complex with?

Answer 3

a TCR ɑβ-chain heterodimer

Question 4

What does TCR require in order to transduce signals?

Answer 4

requires other protein complexes / co-receptors

Question 5

What is ITAM?

Answer 5

Immunoreceptor Tyrosine-based Activation Motif

Question 6

What are γδ TCRs?

Answer 6

T cells which express a γδ-chain dimer

Question 7

How are γδ T cells different from the ɑβ T cells?

Answer 7

usually CD4-CD8
usually not MHC restricted (recognise other molecules)
recognise microbial antigens and/or control integrity/barrier function in epithelia?

Question 8

What is the configuration of TCR genes in cells other than T cells?

Answer 8

germline configuration

Question 9

What have the α + β chain genes undergone in T cells?

Answer 9

somatic rearrangement

Question 10

What do TCR genes show and what does this do?

Answer 10

allelic exclusion and the productive rearrangement (of α + β chains) which blocks further gene rearrangement and results in only one type of TCR per cells

Question 11

What happens since TCR genes do not undergo somatic hypermutation?

Answer 11

there is no change in TCR affinity during activation, differentiation or expansion

Question 12

How do TCR genes rearrange?

Answer 12

so that one of the Vα segments pairs with the Jα segment and a Vβ segment pairs with a Dβ and Jβ segment

Question 13

What determines TCR specificity?

Answer 13

combinations of Va/Ja and Vb/Db/Jb determine specificity

also n-regions (sloppy joins) contribute to specificity (and increases overall diversity)

Question 14

What do the V regions in TCR chains have?

Answer 14

hypervariable regions (or CDRs)

Question 15

What is the role of CDR3 loops of Vα and Vβ?

Answer 15

make the principal contacts with peptide-MHC

Question 16

Do all contact residues contribute equally to TCR/MHC interactions?

Answer 16

no

Question 16

What does TCR associate with to produce a signal across the membrane?

Answer 16

epsilon, delta, gamma and zeta chains

Question 17

How are epsilon, delta, gamma and zeta chains able to produce a signal across the membrane?

Answer 17

involves phosphorylation of ITAMS by tyrosine kinases

phosphorylation enables adaptors and scaffold proteins to drive the signalling cascade and produce activation effects

Question 18

What does the presence of Lck determine?

Answer 18

determines whether the signalling cascade is going to be triggered or not

Question 19

How is Lck regulated?

Answer 19

regulated through phosphorylation and dephosphorylation

this induces changes in conformation

Question 20

When is Lck inactive?

Answer 20

when its terminal tyrosine is phosphorylated and binds the SH2 domain and the linker region binds the SH3 domain

Question 21

What is the role of CD45?

Answer 21

CD45 is a phosphatase and dephosphorylates Tyr residues = primed

Question 21

What is the role of Csk?

Answer 21

Csk is a kinase and phosphorylates Tyr residues = inactive

Question 22

What happens once Lck is primed?

Answer 22

Lck can auto phosphorylate and becomes active

this allows active Lck to phosphorylate ITAMs in the CD3 subunit

Question 23

What happens when Lck phosphorylates ITAMs in the CD3 subunit?

Answer 23

drives further signalling by acting as a docking site for other mediators/enzymes

Question 24

What is the TCR associated with?

Answer 24

a series of ITAM-containing dimeric adaptor molecules

Question 25

What do antigen receptors consist of?

Answer 25

variable antigen-binding chains associated with invariant chains that carry out the signalling function of the receptor

Question 26

What does antigen recognition by the T-cell receptor and its co-receptors transduce?

Answer 26

a signal across the plasma membrane to initiate signalling | binding of the TCR to an MHC/peptide complex recruits Lck to the TCR/CD3 complex

Question 27

What does CD4 and CD8 bind to?

Answer 27

conserved regions of MHC class II and class I respectively

Question 28

What is Lck constitutively associated with?

Answer 28

CD4 and CD8

Question 29

What do phosphorylated ITAMs provide?

Answer 29

a docking site for the activation of ZAP70 which can then phosphorylate other substrates so long as it is active

Question 30

What is the role of activated ZAP-70?

Answer 30

phosphorylates scaffold proteins and promotes activation of different downstream pathways

Question 31

What is CD28?

Answer 31

cell-surface protein CD28 is a required co-stimulatory signalling receptor for naive T-cell activation

Question 32

What is maximal activation of PLC-γ important for and what does it require?

Answer 32

important for transcription factor activation and requires a co-stimulatory signal induced by CD28

Question 33

CD45 knockout mice (lacking functional CD45) are often used to study the development and function of T cells. Why might this be the case?

Answer 33

this is because Lck remains inactive, therefore a signal cascade cannot occur after a TCR-MHC interaction