Lecture 22 - Cytokines and Chemokines Flashcards
What is the mechanism of intercellular crosstalk?
Cytokines
What is the definition of a cytokine?
- Small molecule
- Peptide or protein
- Upon release and binding to specific receptors mediate distinct immunological functions
What are some of the immunological functions of cytokines?
- 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
Describe the mechanism of action of cytokines
- Released by a cell
- Bind to specific receptors on the cell surface
- Transduction pathway, e.g. JAK / STAT pathway
- Gene expression
What is the structure of cytokine receptors?
Where are they located?
• Located on the cell surface
Structure:
• Multimers
• Some chains are shared between different receptors
What type of molecule are cytokines?
Peptide or protein
What is transpresentation?
e.g. IL-15
- IL-15 “transpresented” by DC with IL-15Rα
- Binds to receptor on CTL or NK cell
IL-15Rα needed to elicit a response in the target cells
What is the TNF superfamily?
What are the major functions?
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:
- Inflammation
- Cell survival / growth
What is TNF-α?
What are some of the effects?
Strong pro-inflammatory cytokine
Effects: • Neutrophil activation • Catabolic metabolism • Apoptosis (of tumour cells) • Perpetuation of pro-inflammatory cytokine loops
For which disease does TNF-alpha play an important pathological role?
Treatment?
Rheumatoid arthritis
Infliximab (Remicade, Humira) MAbs against TNF-alpha are a good therapeutic
What is the common γ chain?
Common subunit in cytokine receptors
aka CD132
What are some common γ chain cytokines?
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)
What is the function of IL-2?
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
For what is IL-4 important?
- Differentiation and function of Th2 cells
- IgE class switching
- Role in allergy
For what is IL-7 important?
Central role in T lymphocyte development
For what is IL-9 important?
Activation of • Eosinophils • Mast cells • Endothelium • B cells
For what is IL-15 important?
- NK cell development
* T cell homeostasis
For what is IL-21 important?
Important for Tfh cells: Stimulation of B cell responses in germinal centres
What is a chemokine?
What are the key functions?
“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
How many known chemokines are there?
Around 50
How are chemokines classified?
Cystein residues in the N-terminus
• CC
• CXC
Describe the mechanism of action of chemokines
- Released by cells
- Bind to GPCRs
- Chemotaxis of cell towards source, amoeboid
What is the receptor for CCL19/21?
CCR7
Describe the interaction between CCR7 and CCL19/21
- CCL19/21 constitutively expressed in LNs
- CCR7 expressed on naïve T & B lymphocytes and DCs
- CCR7 expressing cells are guided towards the LNs
Which cells produce CCL19/21?
- LN Stromal cells
* Endothelial cells lining HEVs
What is the ligand for CXCR5?
CXCL13
Describe the interaction between CXCR5 and CXCL13
- 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
What produces CXCL13?
FDCs in B cell follicles
Describe how activated B cells and Tfh cells meet
• 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
Where will CCR7 expression localise a cell?
Compare this with CXCR5
CCR7: T cell zone
CXCR5: B cell follicle
Describe an example of discovery of a cytokine having a clinical application
TNF-α role in Rheumatoid arthritis
mAbs against TNF has been effective in treatment of RA
What was TNF-α called cachexin?
This molecule induces cachexia through stimulation of catabolic metabolism
It is seen clinically in chronic diseases (cancer, infections, AIDS) in which there is wasting
Why is TNF so called?
When added to tumours, the cells die
Is TNF-α anabolic or catabolic?
Suggest a reason this might occur in infection
Catabolic: breaking down of material
Generation of heat → fever → body no longer at the optimal temperature for bacteria
What is CD132?
Common γ chain
Seen in many cytokine receptors
What is seen in individuals who have a mutation in the gene for the common γ chain?
SCID: severe combined immunodeficiency
X-linked, as the common γ chain is encoded on the X chromosome
Compare the structure of the moderate and high affinity IL-2Rs
Where are these found?
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
Compare the size of cytokines and chemokines
Chemokines are much smaller than cytokines
They are often only polypeptides
What are the chemokine receptors?
Which pathway is activated?
GPCRs
→ cAMP pathway stimulated
What is the effect of pertussis toxin?
Block all GPCR
→ block action of all chemokines
When do DCs express CCR7?
Once it encounters foreign antigen
Now the DC is responsive to CCL19/21 and will be attracted to the lymph nodes
What sets up the anatomical structure of lymphoid organs?
Chemokines
e.g.. CCL19/21 expression in paracortex brings T cells to this area
