Lecture 12 - Lymphocyte Activation Flashcards Preview

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Flashcards in Lecture 12 - Lymphocyte Activation Deck (56)
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1

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

1) NFkB
2) NFAT
3) AP-1

2

Function of NFkB, NFAT and AP-1

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

3

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

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

4

Types of CD3 dimers
1)
2)
3)

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

5

ITAM

Immunoreceptor Tyrosine-based Activation Motif

6

ITAM structure

Yxx[L/V]x(6-9)Yxx[L/V]
Where x is any amino acid

7

What phosphorylates Y residues in ITAMS?

Src family kinases
EG: Lck, Fyn

8

Src family regulation

Activation - CD45 removes phosphate from kinase domain
Inactivation - C-terminal Src Kinase (Csk) adds phosphate to kinase domain

9

What phosphorylates Src kinases?

C-terminal Src kinase (Csk)
Phosphorylates C-terminal Y of Src

10

What removes a phosphate from Src kinase?

CD45

11

Examples of Src kinases

Lck
Fyn

12

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

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

13

Lck location

Cell membrane bound
Without CD4/CD8, not complexed with TCR complex

14

What brings Lck into contact with TCR/CD3 complex?

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

15

Lck function

Phosphorylates ITAMs on CD3 complex

16

Src family strucutre

SH3 - SH2 - Kinase domain

17

Syk family structure

SH2 - SH2 - Kinase

18

What is ZAP-70?

A Syk family kinase

19

What recruits ZAP-70?

Phosphorylated ITAM of CD3zeta

20

What does the phosphorylated ITAM of CD3zeta recruit?

ZAP-70

21

ZAP-70 function

Phosphorylates LAT, phospholipase Cgamma

22

What activates Syk family kinases?

SH2 domain interaction with phosphotyrosines on other proteins

23

Example of a Syk family kinase

ZAP-70

24

Proximal signalling events
1)
2)
3)
4)
5)

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

LAT

Linker of T cell Activation

26

Function of LAT

Membrane bound protein which has many tyrosines that can be phosphorylated

Phosphorylated tyrosines provide docking sites for proteins with two SH2 domains

27

Two signalling pathways initiated by phosphorylation of LAT

1) Phospholipase C gamma (PLCgamma)
2) MAP kinase

28

What activates phospholipase C gamma and MAP kinase?

Phosphorylated LAT

29

What phosphorylates LAT?

ZAP-70 bound to TCR proximal signalling complex

30

What activates phospholipase C gamma?

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