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ODDR Immunology > Lecture 12 - Lymphocyte Activation > Flashcards

Lecture 12 - Lymphocyte Activation Flashcards

1
Q

Transcription factors activated by TCR activation
1)
2)
3)

A

1) NFkB
2) NFAT
3) AP-1

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2
Q

Function of NFkB, NFAT and AP-1

A

Transcription factors

All required to bind to promotor for expression of certain genes, EG: IL-12

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3
Q 
Components of complete TCR complex
1)
2)
3)
4)
5)
A

1) TCR
2) CD3 dimers
3) CD8/CD4
4) Lck
5) ZAP-70

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4
Q

Types of CD3 dimers
1)
2)
3)

A

1) Epsilon/Delta dimer
2) Gamma/Delta dimer
3) Zeta homodimer

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5
Q

ITAM

A

Immunoreceptor Tyrosine-based Activation Motif

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6
Q

ITAM structure

A

Yxx[L/V]x(6-9)Yxx[L/V]

Where x is any amino acid

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7
Q

What phosphorylates Y residues in ITAMS?

A

Src family kinases

EG: Lck, Fyn

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8
Q

Src family regulation

A

Activation - CD45 removes phosphate from kinase domain

Inactivation - C-terminal Src Kinase (Csk) adds phosphate to kinase domain

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9
Q

What phosphorylates Src kinases?

A

C-terminal Src kinase (Csk)

Phosphorylates C-terminal Y of Src

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10
Q

What removes a phosphate from Src kinase?

A

CD45

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11
Q

Examples of Src kinases

A

Lck

Fyn

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12
Q

How is Src kinase inhibited?
1)
2)
3)

A

1) C-terminal Src kinase phosphorylates kinase domain of Src kinase
2) Phosphorylated kinase domain bends around, binds to SH2 domain
3) SH2 domain is now prevented from binding to phosphotyrosines

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13
Q

Lck location

A

Cell membrane bound

Without CD4/CD8, not complexed with TCR complex

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14
Q

What brings Lck into contact with TCR/CD3 complex?

A

CD4/CD8 will bind both B2/A3 of TCR (extracellular) and Lck (intracellular)

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15
Q

Lck function

A

Phosphorylates ITAMs on CD3 complex

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16
Q

Src family strucutre

A

SH3 - SH2 - Kinase domain

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17
Q

Syk family structure

A

SH2 - SH2 - Kinase

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18
Q

What is ZAP-70?

A

A Syk family kinase

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19
Q

What recruits ZAP-70?

A

Phosphorylated ITAM of CD3zeta

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20
Q

What does the phosphorylated ITAM of CD3zeta recruit?

A

ZAP-70

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21
Q

ZAP-70 function

A

Phosphorylates LAT, phospholipase Cgamma

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22
Q

What activates Syk family kinases?

A

SH2 domain interaction with phosphotyrosines on other proteins

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23
Q

Example of a Syk family kinase

A

ZAP-70

24
Q 
Proximal signalling events
1)
2)
3)
4)
5)
A

1) MHC molecule provides a docking site for TCR/CD3 complex and CD4/CD8
2) CD4/CD8 binds Lck, bringing Lck into contact with CD3 complex
3) Lck phosphorylates ITAM on CD3zeta
4) ZAP-70 binds to phosphorylated ITAM of CD3zeta
5) Lck phosphorylates ZAP-70

25
Q

LAT

A

Linker of T cell Activation

26
Q

Function of LAT

A

Membrane bound protein which has many tyrosines that can be phosphorylated

Phosphorylated tyrosines provide docking sites for proteins with two SH2 domains

27
Q

Two signalling pathways initiated by phosphorylation of LAT

A

1) Phospholipase C gamma (PLCgamma)

2) MAP kinase

28
Q

What activates phospholipase C gamma and MAP kinase?

A

Phosphorylated LAT

29
Q

What phosphorylates LAT?

A

ZAP-70 bound to TCR proximal signalling complex

30
Q

What activates phospholipase C gamma?

A

ZAP-70 and Ita, when phospholipase C is bound to LAT

31
Q

Phospholipase C gamma function

A

Catalyses the hydrolysis of membrane phospholipids

32
Q

Phospholipase C gamma function in lymphocyte activation

A

Cleaves PIP2 into DAG and IP3

33
Q

PIP2

A

Phosphatidyl inositol bisphosphate

Cleaved into DAG and IP3 by PLCgamma

34
Q

DAG

A

Diacylglycerol

Product of PLCgamma cleaving PIP2

35
Q

IP3

A

Inositol trisphosphate

Product of PLCgamma cleaving PIP2

36
Q

Diacylglycerol function

A

DAG, Ca2+ activate protein kinase C

37
Q

Inositol trisphosphate function

A

Increases intracellular Ca2+

This activates calcineurin

38
Q

Protein kinase C function

A

NFkB activation

39
Q

Calcineurin function

A

NFAT activation

40
Q

What is NFkB?

A

A transcription factor

41
Q

What is NFAT?

A

A transcription factor

42
Q

NFkB regulation
1)
2)
3)

A

1) Normally, NFkB is a dimer in the cytosol, bound to Inactive kB (IkB)
2) Protein kinase C phosphorylates IkB, causing IkB to be degraded in proteosome
3) This allows NFkB to enter the nucleus, act as a transcription factor

43
Q

IkB function

A

Binds to NFkB dimer in the cytoplasm

Prevents NFkB entry into the nucleus

44
Q

What kind of regulation are NFkB and NFAT subject to?

A

Location-dependent regulation

45
Q 
NFAT regulation
1)
2)
3)
4)
A

1) NFAT is normally phosphorylated, which prevents it from entering the nucleus
2) When IP3 raises intracellular [Ca2+], calmodulin on calcineurin is activated
3) Calcineurin removes phosphate from NFAT
4) NFAT enters the nucleus, binds to promotor

46
Q

Calcineurin

A

A phosphatase

Activated by elevated intracellular [Ca2+]

47
Q

Cyclosporine function

A

Binds to calcineurin, prevents it from dephosphorylating NFAT

Immunosuppressant

48
Q

Clinical use of cyclosporine

A

Transplants

49
Q 
Generic MAP kinase pathway
1)
2)
3)
4)
5)
A

1) Guanine nucleotide exchange factor (SOS) activates a small G protein (ras, rac)
2) Activated small G protein activates a MAP kinase kinase kinase
3) Map kinase kinase kinase activates MAP kinase kinase
4) MAP kinase kinase activates MAP kinase
5) MAP kinase activates transcription factors (EG: Elk)

50
Q

Example of a guanine nucleotide exchange factor

A

SOS

51
Q

Example of a MAP kinase kinase kinase

A

Raf

52
Q

Example of a MAP kinase kianse

A

Mak

53
Q

Example of a MAP kinase

A

Erk

54
Q

How does TCR binding activate MAP K?
1)
2)
3)

A

1) Phosphorylated LAT recruits Grb2
2) Grb2 recruits SOS
3) SOS activates ras GTPase

55
Q

Which gene promotor does Elk bind to?

A

AP-1

Promotes AP-1 transcription

56
Q

Proportion of required AP-1 transcription caused by Elk

A

1/2
Other half is caused by costimulation by CD80, CD86, CD28
A checkpoint mechanism to prevent T cell overactivity

ODDR Immunology (31 decks)

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