Lecture 12: T Cell Receptor Genetics, Structure, Functional Recognition and Signalling Flashcards
What are important properties of the TCR?
recognises MHC:peptide complex
Ig-like molecule expressed on T cells
only one TCR specific per T cell
What is the structure of a TCR?
consists of Ig-like domains which are about 100aa long
consists of an ɑ- and β-chain
What do most T cells recognise the peptide/MHC complex with?
a TCR ɑβ-chain heterodimer
What does TCR require in order to transduce signals?
requires other protein complexes / co-receptors
What is ITAM?
Immunoreceptor Tyrosine-based Activation Motif
What are γδ TCRs?
T cells which express a γδ-chain dimer
How are γδ T cells different from the ɑβ T cells?
usually CD4-CD8
usually not MHC restricted (recognise other molecules)
recognise microbial antigens and/or control integrity/barrier function in epithelia?
What is the configuration of TCR genes in cells other than T cells?
germline configuration
What have the α + β chain genes undergone in T cells?
somatic rearrangement
What do TCR genes show and what does this do?
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
What happens since TCR genes do not undergo somatic hypermutation?
there is no change in TCR affinity during activation, differentiation or expansion
How do TCR genes rearrange?
so that one of the Vα segments pairs with the Jα segment and a Vβ segment pairs with a Dβ and Jβ segment
What determines TCR specificity?
combinations of Va/Ja and Vb/Db/Jb determine specificity
also n-regions (sloppy joins) contribute to specificity (and increases overall diversity)
What do the V regions in TCR chains have?
hypervariable regions (or CDRs)
What is the role of CDR3 loops of Vα and Vβ?
make the principal contacts with peptide-MHC
Do all contact residues contribute equally to TCR/MHC interactions?
no
What does TCR associate with to produce a signal across the membrane?
epsilon, delta, gamma and zeta chains
How are epsilon, delta, gamma and zeta chains able to produce a signal across the membrane?
involves phosphorylation of ITAMS by tyrosine kinases
phosphorylation enables adaptors and scaffold proteins to drive the signalling cascade and produce activation effects
What does the presence of Lck determine?
determines whether the signalling cascade is going to be triggered or not
How is Lck regulated?
regulated through phosphorylation and dephosphorylation
this induces changes in conformation
When is Lck inactive?
when its terminal tyrosine is phosphorylated and binds the SH2 domain and the linker region binds the SH3 domain
What is the role of CD45?
CD45 is a phosphatase and dephosphorylates Tyr residues = primed
What is the role of Csk?
Csk is a kinase and phosphorylates Tyr residues = inactive
What happens once Lck is primed?
Lck can auto phosphorylate and becomes active
this allows active Lck to phosphorylate ITAMs in the CD3 subunit
What happens when Lck phosphorylates ITAMs in the CD3 subunit?
drives further signalling by acting as a docking site for other mediators/enzymes
What is the TCR associated with?
a series of ITAM-containing dimeric adaptor molecules
What do antigen receptors consist of?
variable antigen-binding chains associated with invariant chains that carry out the signalling function of the receptor
What does antigen recognition by the T-cell receptor and its co-receptors transduce?
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
What does CD4 and CD8 bind to?
conserved regions of MHC class II and class I respectively
What is Lck constitutively associated with?
CD4 and CD8
What do phosphorylated ITAMs provide?
a docking site for the activation of ZAP70 which can then phosphorylate other substrates so long as it is active
What is the role of activated ZAP-70?
phosphorylates scaffold proteins and promotes activation of different downstream pathways
What is CD28?
cell-surface protein CD28 is a required co-stimulatory signalling receptor for naive T-cell activation
What is maximal activation of PLC-γ important for and what does it require?
important for transcription factor activation and requires a co-stimulatory signal induced by CD28
CD45 knockout mice (lacking functional CD45) are often used to study the development and function of T cells. Why might this be the case?
this is because Lck remains inactive, therefore a signal cascade cannot occur after a TCR-MHC interaction
