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MIIM30002 - Principles of Immunology > Lecture 22 - Cytokines and Chemokines > Flashcards

Lecture 22 - Cytokines and Chemokines Flashcards

1
Q

What is the mechanism of intercellular crosstalk?

A

Cytokines

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2
Q

What is the definition of a cytokine?

A
  • Small molecule
  • Peptide or protein
  • Upon release and binding to specific receptors mediate distinct immunological functions
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3
Q

What are some of the immunological functions of cytokines?

A
  • Intercellular signalling, e.g. IL-7
  • Autocrine feedback loops e.g. IL-2
  • Promotion of release of other cytokines, e.g. IL-2
  • Inhibition of the release of other cytokines, e.g. IL-10
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4
Q

Describe the mechanism of action of cytokines

A
  1. Released by a cell
  2. Bind to specific receptors on the cell surface
  3. Transduction pathway, e.g. JAK / STAT pathway
  4. Gene expression
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5
Q

What is the structure of cytokine receptors?

Where are they located?

A

• Located on the cell surface

Structure:
• Multimers
• Some chains are shared between different receptors

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6
Q

What type of molecule are cytokines?

A

Peptide or protein

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7
Q

What is transpresentation?

A

e.g. IL-15

  1. IL-15 “transpresented” by DC with IL-15Rα
  2. Binds to receptor on CTL or NK cell

IL-15Rα needed to elicit a response in the target cells

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8
Q

What is the TNF superfamily?

What are the major functions?

A

19 structurally related protein ligands
Bind to one or more receptors
A given receptor will be bound by many ligands in the TNF superfamily

Functions:

  1. Inflammation
  2. Cell survival / growth
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9
Q

What is TNF-α?

What are some of the effects?

A

Strong pro-inflammatory cytokine

Effects:
 • Neutrophil activation
 • Catabolic metabolism
 • Apoptosis (of tumour cells)
 • Perpetuation of pro-inflammatory cytokine loops
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10
Q

For which disease does TNF-alpha play an important pathological role?

Treatment?

A

Rheumatoid arthritis

Infliximab (Remicade, Humira) MAbs against TNF-alpha are a good therapeutic

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11
Q

What is the common γ chain?

A

Common subunit in cytokine receptors

aka CD132

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12
Q

What are some common γ chain cytokines?

A 
IL-2
IL-4
IL-7
IL-9
IL-15
IL-21

These all bind to cytokine receptors which contain the common γ chain (CD132)

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13
Q

What is the function of IL-2?

A

T cell growth factor

  • Following T cell activation, IL-2 expression is up-regulated
  • IL-2 binds to IL-2R on T cell
  • Autocrine signalling
  • T cell enters cell cycle and proliferates rapidly
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14
Q

For what is IL-4 important?

A
  • Differentiation and function of Th2 cells
  • IgE class switching
  • Role in allergy
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15
Q

For what is IL-7 important?

A

Central role in T lymphocyte development

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16
Q

For what is IL-9 important?

A 
Activation of
 • Eosinophils 
 • Mast cells
 • Endothelium
 • B cells
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17
Q

For what is IL-15 important?

A
  • NK cell development

* T cell homeostasis

18
Q

For what is IL-21 important?

A

Important for Tfh cells: Stimulation of B cell responses in germinal centres

19
Q

What is a chemokine?

What are the key functions?

A

“Chemotactic cytokine”

Functions:
• Recruitment of circulating leukocytes from blood into tissues
• Regulation of traffic of lymphocytes through lymphoid organs
• Migration of DCs from tissues into LNs

20
Q

How many known chemokines are there?

A

Around 50

21
Q

How are chemokines classified?

A

Cystein residues in the N-terminus
• CC
• CXC

22
Q

Describe the mechanism of action of chemokines

A
  1. Released by cells
  2. Bind to GPCRs
  3. Chemotaxis of cell towards source, amoeboid
23
Q

What is the receptor for CCL19/21?

A

CCR7

24
Q

Describe the interaction between CCR7 and CCL19/21

A
  • CCL19/21 constitutively expressed in LNs
  • CCR7 expressed on naïve T & B lymphocytes and DCs
  • CCR7 expressing cells are guided towards the LNs
25
Q

Which cells produce CCL19/21?

A
  • LN Stromal cells

* Endothelial cells lining HEVs

26
Q

What is the ligand for CXCR5?

A

CXCL13

27
Q

Describe the interaction between CXCR5 and CXCL13

A
  • CXCL13 produced in B cell follicles
  • Naïve B cells express CXCR5
  • Naïve B cells attracted towards B cell follicle
  • Activated B cell start expressing CCR7 as well, so that they migrate to the T-B cell border
  • Tfh express both CXCR5 & CCR7, so they migrate to the T-B cell border
28
Q

What produces CXCL13?

A

FDCs in B cell follicles

29
Q

Describe how activated B cells and Tfh cells meet

A

• Upon activation B cells start expressing CCR7 (in addition to CXCR5)
→ migration towards paracortex

• Tfh start expressing CXCR5 (in addition to CCR7)
→ migration towards B cell follicle

The two cells meet in the middle in the marginal zone

30
Q

Where will CCR7 expression localise a cell?

Compare this with CXCR5

A

CCR7: T cell zone

CXCR5: B cell follicle

31
Q

Describe an example of discovery of a cytokine having a clinical application

A

TNF-α role in Rheumatoid arthritis

mAbs against TNF has been effective in treatment of RA

32
Q

What was TNF-α called cachexin?

A

This molecule induces cachexia through stimulation of catabolic metabolism

It is seen clinically in chronic diseases (cancer, infections, AIDS) in which there is wasting

33
Q

Why is TNF so called?

A

When added to tumours, the cells die

34
Q

Is TNF-α anabolic or catabolic?

Suggest a reason this might occur in infection

A

Catabolic: breaking down of material

Generation of heat → fever → body no longer at the optimal temperature for bacteria

35
Q

What is CD132?

A

Common γ chain

Seen in many cytokine receptors

36
Q

What is seen in individuals who have a mutation in the gene for the common γ chain?

A

SCID: severe combined immunodeficiency

X-linked, as the common γ chain is encoded on the X chromosome

37
Q

Compare the structure of the moderate and high affinity IL-2Rs
Where are these found?

A

Moderate affinity IL-2R: naïve T cells
• alpha subunit not present
• less potent response in the cell

High affinity:
• in activated T cells
• highly potent response in the T cell

38
Q

Compare the size of cytokines and chemokines

A

Chemokines are much smaller than cytokines

They are often only polypeptides

39
Q

What are the chemokine receptors?

Which pathway is activated?

A

GPCRs

→ cAMP pathway stimulated

40
Q

What is the effect of pertussis toxin?

A

Block all GPCR

→ block action of all chemokines

41
Q

When do DCs express CCR7?

A

Once it encounters foreign antigen

Now the DC is responsive to CCL19/21 and will be attracted to the lymph nodes

42
Q

What sets up the anatomical structure of lymphoid organs?

A

Chemokines

e.g.. CCL19/21 expression in paracortex brings T cells to this area

MIIM30002 - Principles of Immunology (30 decks)

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