T cell antigen dscrimination

Question 1

estimated of number of possible TCRs?

Answer 1

10^15

Question 2

estimate of number of T cellsin periphery? And how many unique TCRs?

Answer 2

10^12 T cells in periphery, with only 10^8 TCRs, due to homeostatic proliferation of T cells.

Question 3

Paradox of TCR recognition of self and foreign pMHCs on same APC? e.g. What is antigen discrimination?

Answer 3

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.

Question 4

3 ways you can measure the response of T cells to antigens at different concentrations?

Answer 4

1. T cell proliferation. 2) production of IL-2. 3) levels of signalling molecule phosphorylated ppERK.

Question 5

What kind of pertubations of a single amino acid change of a pMHC affect?

Answer 5

Can affect he charge and surface complimentaritiy which pertubs the binding interaface

Question 6

what is dissociation constant a ratio of?

Answer 6

the time in k off/k on

Question 7

what does a lower and a higher kd mean?

Answer 7

Lower Kd means a higher bindin gaffinitiy. higher Kd means a lower binding affinity.

Question 8

What is the dissociation time qeuation?

Answer 8

1/Koff, and is the lifetime in secondads that MHC is bound?

Question 9

If TCRs are not specific for a single peptide, what are they specific for?

Answer 9

They could be specific for pMHC binding parameters, and require a threshold affinity or koff for activation.

Question 10

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?

Answer 10

Cannot cmopensate for lower pMHC afffinity by increasing the concentration of pMHC.

Question 11

What is the occupancy model?

Answer 11

That T cell activation can be determined by how many TCRs are bound by pMHC. Therefore increasing pMHC concentration could compensate for lower affinity.

Question 12

What is the kinetic proofreading model?

Answer 12

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.

Question 13

why did high sensitivity to a single pMHC evolve?

Answer 13

Becuase copy number of pMHC is low on APCs.

Question 14

How do we konw T cells have high sensitivity?

Answer 14

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.

Question 15

How does increasing pMHCs increase T cell activation?

Answer 15

By increasing the proportion (probability) that T cells respond to pMHCs.

Question 16

What contributes to the tension that almost pulls TCR: pMHCs complexes apart?

Answer 16

The actin cytoskeleton, and also the larger bulkier proteins.

Question 17

Why is such high TCR sensitivity surprising/ paradoxical?

Answer 17

Because TCR:pMHC interactions have a short lifetime. But you need TCR:pMHC interactions to occur over a long time for robust activation.

Question 18

What active processes keep TCR:pMHCs in close proximity for interaction?

Answer 18

T cells form dynamic microvilli with TCRs at the tip.

Question 19

What two R/L adhesion interactions help keep TCR: pMHC in close proximity?

Answer 19

T cell then APC.
LFA-1: ICAM-1 and CD2: CD58.
CD2:CD58 interaction is same intermembrane distance between TCR:pMHC.

Question 20

What does a longer delay in proofreading do for specificity?

Answer 20

Will increase probability that only higher affinity TCR: pMHC interactions remain. Increasing specificity.

Question 21

What does longer delay in proofreading do for sensitivity?

Answer 21

Will decrease probabilyt that even the highest affinity pMHCs remain bound, decreasing sensitivity.