T cell antigen dscrimination Flashcards
estimated of number of possible TCRs?
10^15
estimate of number of T cellsin periphery? And how many unique TCRs?
10^12 T cells in periphery, with only 10^8 TCRs, due to homeostatic proliferation of T cells.
Paradox of TCR recognition of self and foreign pMHCs on same APC? e.g. What is antigen discrimination?
Must weakly bind self pMHCs for tonic signalling and survival. But must ignore the large number of self antigens and focus on the low (1-50) foreign pMHCs on the SAME APC.
3 ways you can measure the response of T cells to antigens at different concentrations?
- T cell proliferation. 2) production of IL-2. 3) levels of signalling molecule phosphorylated ppERK.
What kind of pertubations of a single amino acid change of a pMHC affect?
Can affect he charge and surface complimentaritiy which pertubs the binding interaface
what is dissociation constant a ratio of?
the time in k off/k on
what does a lower and a higher kd mean?
Lower Kd means a higher bindin gaffinitiy. higher Kd means a lower binding affinity.
What is the dissociation time qeuation?
1/Koff, and is the lifetime in secondads that MHC is bound?
If TCRs are not specific for a single peptide, what are they specific for?
They could be specific for pMHC binding parameters, and require a threshold affinity or koff for activation.
For most other receptor ligand interactions, you could compensate for lowering affinity of receptor by increasing the concentration of ligand. Is this the case for TCRs?
Cannot cmopensate for lower pMHC afffinity by increasing the concentration of pMHC.
What is the occupancy model?
That T cell activation can be determined by how many TCRs are bound by pMHC. Therefore increasing pMHC concentration could compensate for lower affinity.
What is the kinetic proofreading model?
Signalling is not immediate, activation signalling relies on ligand to be bound for a threshold period of time. If not, then resets to basal level. This means increasing pMHC concentration cannot compensate for low binding affinity.
why did high sensitivity to a single pMHC evolve?
Becuase copy number of pMHC is low on APCs.
How do we konw T cells have high sensitivity?
T cellls interacting with APCs with a single pMHC exhibited same amounts f TNF-a as those APCs with 2 or 3 or 4 pMHCs.
How does increasing pMHCs increase T cell activation?
By increasing the proportion (probability) that T cells respond to pMHCs.
What contributes to the tension that almost pulls TCR: pMHCs complexes apart?
The actin cytoskeleton, and also the larger bulkier proteins.
Why is such high TCR sensitivity surprising/ paradoxical?
Because TCR:pMHC interactions have a short lifetime. But you need TCR:pMHC interactions to occur over a long time for robust activation.
What active processes keep TCR:pMHCs in close proximity for interaction?
T cells form dynamic microvilli with TCRs at the tip.
What two R/L adhesion interactions help keep TCR: pMHC in close proximity?
T cell then APC.
LFA-1: ICAM-1 and CD2: CD58.
CD2:CD58 interaction is same intermembrane distance between TCR:pMHC.
What does a longer delay in proofreading do for specificity?
Will increase probability that only higher affinity TCR: pMHC interactions remain. Increasing specificity.
What does longer delay in proofreading do for sensitivity?
Will decrease probabilyt that even the highest affinity pMHCs remain bound, decreasing sensitivity.
