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MEDSCI 314 > Lecture 15; T cell activation and effector subsets > Flashcards

Lecture 15; T cell activation and effector subsets Flashcards

1
Q

Describe the antigen binding site on the tcR;

A

The hypervariable region can be;

  • a/b

or

  • g/d

TcR’s

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2
Q

What do the TcR recognise?

A

MHC molecules only

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3
Q

Describe the CD3 complex signalling proteins;

A

Four seperate chains that can be Phosphorylated

g,d,epsilom, zeta

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4
Q

What is the t cell antigen receptor complex?

A

CD4

CD3
TcR
CD3

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5
Q

What are CD4 and CD8 and what do they both have in common for signalling?

A

Co receptors of TcR

They both have Src Kinases called Lck

Bound non-covalently to their IC domains

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6
Q

During exogeous activation, what second signal must t cells recieve?

A

T cells must recieve a second signal via the CD28

CD28 binds CD80,86 on APC

This is absolutely essential for Tcell activation

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7
Q

What are important T cell adhesion molecules?

A

LFA1-ICAM-1

CD2-LFA3

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8
Q

What are the key protein kinases for T cell intracellular signalling;

A

Protein Tyrosine Kinases;

  • Lck
  • ZAP70
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9
Q

What is a tyrosine phosphotase involved in the regulation of t cell?

A

CD45 (tyrosine phosphotase)

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10
Q

What down regulates the t cell response?

A

CTLA-4 can outcompete CD28 preventing t cell signalling

Also results in RAS upregulation and apoptosis

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11
Q

what is a SMAC?

A

Supramolecular Activation Clusters

Molecules that are colocated to the membrane during T cell activation

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12
Q

What is in a SMAC?

A
  • TcR + CD3 (antigen recognition)
  • CD3 g,d,e,z (signalling)
  • CD4 or CD8 (coreceptor)
  • Costimulatory molecule (CD28) (Stim) CTLA-4 (inhib)
  • Kinases (Lck, ZAP70)
  • Adhesion molecules (LFA1-ICAM-1 & CD2-LFA3)
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13
Q

What can cause dysregulation of smac?

A

CTLA-4 or SHP

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14
Q

What is the function of SMACs?

A
  • Increase proximal activity or internal kinases to TcR
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15
Q

Describe SMAC formation;

A

Microclusters are formed first then congeal into one large cluster.

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16
Q

Describe CD3 gamma;

A

IG like membrane domains with short cytoplasmic tail

Non-covalently associates with a/b (TCR)

Contains 1 ITAM

Each CD3 is similar
CD3g> CD3d>CD3e>CD3z

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17
Q

Describe CD3 delta;

A

IG like membrane domains with short cytoplasmic tail

Ive charge in transmembrane domain

Contains 1 ITAM

(same as CD3 e)

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18
Q

Describe CD3 e;

A

IG like membrane domains with short cytoplasmic tail

Ive charge in transmembrane domain

Contains 1 ITAM

Same as CD3 d

(structure will be different)

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19
Q

Describe CD3 z;

A
  • 9 AA EC domain
  • Homodimer
  • 2x3 ITAMS
  • Phosphorylated by Lck and is associated with CD4/8
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20
Q

What is the CD3/TcR complex?

A

A dimer

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21
Q

How is CD3 and TcR unusual?

A

They all have charge AA residues in their TM domains, thus form complexes of dimers

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22
Q

Where is Lck found?

A
  • Lck belongs to the Src family of PTK
  • Lck is bound non-covalently to CD4/CD8 cytoplasmic tail
  • Phosphorylates CD3 ζ-chain ITAM
23
Q

What regulates Lck?

A
  • Regulation:
  • Csk phosphorylates negatively regulate
  • CD45 dephosphorylates to activate
24
Q

What are ITAMs?

A

Immunoreceptor Tyrosine-based Activation Motif

25
Q

What do ITAMs do?

A

IC domain of TCR

  • Binds Src family kinases, e.g. Syk, ZAP-70 - - Recruits signalling proteins that have tandem SH2 domains
26
Q

What are ITIM?

A

Immunoreceptor Tyrosine-based Inhibition Motif Inhibitory receptors

27
Q

What do ITIMS do?

A
  • Binds SHP-1 and SHP-2 phosphatases via SH2 domain.
  • Binds SHIP – ionosotide phosphatase targets IP3
  • Dephosphorylates kinases associated with ITAMs
  • CTLA-4 on T cells – directly opposes CD28
28
Q

What are 1-3 of the earliest events in t cell activation?

A
  1. CD45 is a phosphatase that primes lck by removing phosphate
  2. CD4/CD8 bring Src kinase (lck) proximal to the CD3 ζ-chain
  3. At least 2 ITAMs phosphorylated on ζ−ζ-chain.
29
Q

What are 4-6 of the earliest events in T cell activation?

A
  1. Syk/ZAP70 protein kinase binds phosphorylated ζ-chain via its SH2 domain. 5.Phosphorylation of many adaptor proteins including LAT and SLP-76.
  2. Phospholipase C-γ docks onto phosphorylated LAT-SLP-76.
30
Q

What are 7-9 of the earliest events in T cell activation?

A
  1. PLC-γ cleaves PIP2 to IP3 and DAG.
  2. DAG activates PKC-θ and RasGRP-Ras pathway
  3. IP3 mediates an increase in Ca2+ and activation of the Ser Thr phosphatase calcineurin
31
Q

What happens once a t cell is activated?

A
  • Actin reorganisation (cell enlarges)
  • Cell adhesion molecule upregulation
  • Gene expression and t cell regulation
32
Q

What genes are turned on in t cell activation?

A
  • NFκB (Transcription factor)
  • NF-AT(turns on IL-2 gene)
  • AP-1 (binds IL-2 promoter)

Nuclear translocation of NF-AT, N F-κB and AP-1 to induce specific gene transcription, proliferation and differentiation

33
Q

What turns on NFkB?

A
  • DAG activates PKC-θ

* PKC-θ activates NF-κB

34
Q

What activates NF-AT?

A
  • IP3 increases Ca2+
  • Ca2+ binds Calmodulin
  • Activates Calcineurin phosphatase
  • Calcineurin de-phosphorylates NF-ATc
35
Q

What activates AP-1?

A
  • Guanine exchange factors (GEF) activate Ras
  • Ras activates MAP kinase cascade
  • MAP kinase activates c-Fos component of AP-1
36
Q

What is IL2 to T cells?

A

Key growth factor

37
Q

What pathways do cd28 activate?

A

PKC
RAS-GRP

Thus IL2 = growth and expansion of t cells

38
Q

What does CTLA4 do signalling pathways exactly?

A
  • Dephosphorylates TcR

- Exclusion or endocytosis of CD28 (cant activate PKC)

39
Q

What are the different t cells subsets (cd4) that can arise from activation and proliferation?

A
  • IFN g cytokine = TH1 synthesis
  • IL 4 = TH2
  • TGF-b and IL6 = TH17
40
Q

What causses different t cells subsets to arise?

A

The types of PRR that are activated during infection

Determines cytokine release

41
Q

What do TH1 do?

A

Clearance of intracellular pathogens

immunopathology

Autoimmune

Basically activates CD8

42
Q

What does TH2 do?

A
  • Clearance of EC pathogens
  • Allergy
  • Atopy

i.e IL 6 release!

43
Q

Whats the role of TH17?

A
  • il17 production
  • Clearance of pathogens
  • Tissue inflammation
  • immunopathology, Autoimmunity.
44
Q

What is another t cell that can be produced under certain circumstances?

A

iTreg

If food or self is presented then this mechanism prevents self reaction

TNF-b

45
Q

How can t cells be manipulated?

A 
•  Therapeutic purposes: Organ transplantation
– Cyclosporin
 – FK506
 •  Manipulation by pathogens
– Bacterial and viral superantigens 
•  A clinical trial gone wrong 
– CD28 superantagonist
46
Q

What is alloreactivity?

A

How t cells respond to foreign MHC and to what degree.

47
Q

What does cyclosporin do?

A

Inhibits the translocation of Nuclear Factor for activated T cells (NF-AT )

(inhibits t cells)

48
Q

What does FK-506 (Tacrolimus) do?

A

Also inhibits the translocation of Nuclear Factor for activated T cells (NF-AT )

49
Q

What is the Mechanism of action of cyclosporin & tacrolimus?

A

Both target calcinueron and prevent NF-AC from being phosphorylated and activating IL2

50
Q

What produces super antigens?

A

• Superantigens are produced by bacteria, mycoplasma and viruses,
e.g.:
– staphylococcal enterotoxins (SEs): food poisoning
– Toxic shock syndrome toxin-1 (TSST-1): toxic shock syndrome

51
Q

What do superantigens do?

A
  • Recognised by T cells without processing into peptides

* Can stimulate 2-20% of all T cells = cytokine storm

52
Q

What did CD28 superagonist do?

A

TGN1412 acted like a superantigen and nearly killed people

53
Q

What do PRR do in t cell activation?

A

• PRR (danger) signalling provides context for T cell effector activation

MEDSCI 314 (28 decks)

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