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micr 386 > module 04 section 03 (TCR activation) > Flashcards

module 04 section 03 (TCR activation) Flashcards

1
Q

following antigen processing, peptides are:

A

stably bound to the polymorphic aa anchor residues within the MHC binding cleft for antigen presentaion

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2
Q

recall: do T-cells have single or dual specificity?

A

dual:

  • the CDR1/2 of the TCR bind to the polymorphic residues of self-MHC molecules
  • CDR3 of the TCR binds to the specific residues of the peptide
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3
Q

with respect to TCR, what is a crucial step of T-cell activation?

A

the specific binding of TCR to the MHC:peptide complex

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4
Q

what signals does a naive T-cell require to become fully activated?

A

a pre-signal and 3 extracellular signals

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5
Q

what must occur for the 3 extracellular signals to occur?

A

the T-cell and APC need to be close in proximity, which involves adhesion of the helper T-cell to the APC

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6
Q

the helper T-cell adheres to the APC through?

A

the binding of adhesion molecules:

  • CD2/LFA-3
  • LFA-1/ICAM
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7
Q

what is CD2? where is it found?

A

cell adhesion molecule found on the surface of T-cells and NK cells

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8
Q

what is LFA-3? where is it found?

A

cell adhesion molecule expressed on antigen presenting cells, particularily macrophages

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9
Q

what is LFA-1? where is it found?

A
  • cell adhesion molecule found on lymphocytes

- plays key role in emigration (process of leaving the bloodstream and entering tissue)

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10
Q

what is ICAM-1? where is it found?

A

cell adhesion molecule expressed on antigen presenting cells

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11
Q

what is done to stabilize the adhesion process of T-cells to APCs?

A

the CD4 coreceptor binds to MHC class II on the APC

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12
Q

what family of molecules does LFA-1 belong to?

A

integrin

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13
Q

what family of molecules does LFA-3 belong to?

A

Ig superfamily

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14
Q

recall: what is the pre-signal?

A

adhesion of helper T-cell to the APC

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15
Q

what is the 1st extracellular signal?

A

antigen recognition:

  • TCR recognizes the peptide:MHC complex
  • this low affinity TCR-MHC interaction is stabilized by the adhesion molecules which form a synapse
  • the synapse consists of the adhesion molecules moving and encircling the TCR-peptide:MHC complex for ~10 mins
  • each peptide:MHC complex can sequentially engage w up to 200 TCRs on a T-cell in a process called serial triggering
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16
Q

what is the 2nd extracellular signal?

A

co-stimulatory molecules:

involves the binding of (non-specific) costimulatory molecules B7/CD28 or CD22/CD45R

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17
Q

what is B7? where is it found?

A
  • proliferatory membrane protein found on activated antigen presenting cells
  • there’s two types: B7-1 and B7-2
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18
Q

what is CD28? where is it found?

A

protein expressed on T-cells that provides co-stimulatory signals that provide T-cell activation and survival

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19
Q

what is CD22? where is it found?

A

sugar binding transmembrane protein that binds sialic acid and functions as an inhibitory receptor for B-cell receptor signalling
found on the APCs

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20
Q

what is CD45R? where is it found?

A
  • member of the protein tyrosine phosphatase fam

- expressed on B-cells at all developmental stages and some T-cells

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21
Q

do APCs have similar or differential expression of co-stimulatory signals?

A

differential

22
Q

describe the expression of co-stimulatory signals for dendritic cells

A

consecutive expression of B7

constantly expressed on the cell surface

23
Q

describe the expression of co-stimulatory signals for macrophages

A

inducible expression of B7

24
Q

describe the expression of co-stimulatory signals for B-cells

A

inducible expression of B7

25
Q

can co-stimulatory singals be excitatory? inhibitory?

A

yes for both

26
Q

what differentiates B7-1 from B7-2?

A

B7-2 expresses an intracellular phosphate group

27
Q

the binding of B7-1 to CD28 elicits _____ signals

A

stimulatory

28
Q

the binding of B7-2 to CTLA-4 elicits _____ signals

A

inhibitory

29
Q

what is the 3rd extracellular signal?

A

effector cell function:

  • involves preformance of the cell effector function
  • TCR activation induces helper T-cells to produce cytokines that perform the effector function of the T-cell
  • same thing occurs for cytotoxic T-cells
30
Q

what is the result of successful extracellular signalling?

A

the promotion of a cascade of intracellular signalling to activate T-cells through the TCR/CD3

31
Q

what are tyrosine-based activation motifs (ITAMs)?

A

conserved sequences contained by the cytoplasmic domains of CD3 molecules

32
Q

what do ITAMs contain?

what role do these play?

A

ITAMs contain tyrosine residues that are phosphorylated by protein tyrosine kinases

33
Q

of all of the TCR/CD3 complexes, how many are homodimers and how many are heterodimers?

A

90% homo (ζ,ζ)

10% hetero (ζ,η)

34
Q

recall: what are the key players in intracellular singalling of the TCR/CD3 complex? (2)

A

tyrosine kinases and phosphatase

35
Q

what is a kinase?

A

enzyme that catalyses the transfer of a phosphate group from ATP to a specific molecule

36
Q

what is a phospatase?

A

enzyme that catalyses the hydrolysis of organic phosphates in a specified environment

37
Q

what are the specific tyrosine kinases involved in intracellular signalling? (3)

A

ZAP-70
Fyn
Lck

38
Q

what is ZAP-70?

A

protein normally expressed near the surface membrane of T-cells

39
Q

what is Fyn?

A
  • protein tyrosine kinase

- involved in the regualtion of cell morphology

40
Q

what is Lck?

A
  • protein tyrosine kinase found in T-cells

- most commonly associated with cytoplasmic tails of CD4 and CD8 co-receptors

41
Q

what is step 1 of intracellular singalling for TCR activation?

A
  • simultaneous binding of TCR and CD3 to the peptide:MHC complex results in the close proximity of Lck and Fyn on the ITAMs of CD3
  • the kinases are unable to phosphorylate the ITAM tyrosine residues due to the presence of inhibitory phosphate grps
42
Q

what is step 2 of intracellular singalling for TCR activation?

A
  • binding of CD22 to CD45R activates the protein tyrosine phosphatase on the cytoplasmic tail of CD45R
  • the phosphatase cleaves the inhibitory phosphate grps on Lck and Fyn
43
Q

what is step 3 of intracellular singalling for TCR activation?

A

activated Lck and Fyn kinases phosphorylate the ITAM residues on CD3-ζε

44
Q

what is step 4 of intracellular singalling for TCR activation?

A

the phosporylated CD3ζ chain ITAM residues act as docking sites for ZAP-70, allowing it to bind to CD3ζ and become activated

45
Q

what is step 5 of intracellular singalling for TCR activation?

A

activated ZAP-70 and fyn kinases phosphorylate phospholipase C-γ1 (PLC-γ1) in the plasma membrane of the T-cell

46
Q

what is step 6 of intracellular singalling for TCR activation?

A

acitvated PLC-γ1 cleaves phosphatidylinositol-4-5-biphosphate (PIP2) into inositol triphosphate (IP3) and diacylglycerol (DAG) - which activate transcription factors, NF-AT and NF-kB, respecitvely

47
Q

what is step 7 of intracellular singalling for TCR activation?

A
  • IP3 diffuses through the cytoplasm and binds to IP3-sensitive Ca channels, releasing intracellular Ca stores
  • increased intracellular Ca concentration promotes protein kinase C expression on the plasma membrane
  • prot. kinase C expressed on plasma membrane can be activated by DAG
48
Q

what is step 8 of intracellular singalling for TCR activation?

A
  • the increase of intracellular ca from the activation of IP3 sensitive CA channels also promoted binding of Ca to calmodulin
  • calmodulin then activates calcineurin phosphatase which dephosorylates a family of transcription factors, including NF-AT
  • NF-AT translocates into the nucelus and binds to the NF enhancer region on the IL-2 gene
49
Q

what is step 9 of intracellular singalling for TCR activation?

A
  • prot kinase C activated by DAG phosphorylates an inhibitory factor, releasing transcription factor NF-kB
  • NF-KB then translocates to the nucleus and dimerizes with another IL-2 enhancing region
50
Q

recap: what does the TCR signalling cascade ultimately lead to?

A

the enhanced transcription of the IL-2 gene

51
Q

the production of IL-2 within the activated T-cell promotes what?

A

proliferation and differentiation of the T-cell into effector and memory T-cells

micr 386 (31 decks)

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