1. M1 – Immunology CYTOKINES AND CHEMOKINES March 26, 2009 Ronald B
M1 – Immunology CYTOKINES AND CHEMOKINES March 26, 2009 Ronald B. Smeltz, Ph.D.

2. Learning Objectives 1. Define the term cytokine
2. Recognize and understand the difference between a cytokine and chemokine
3. Discuss the mode-of-action for cytokines
4. Know the functions of TGF-, TNF, and IFN-
5. Contrast the roles of IL-12 and IL-10 in inflammation
6. Predict the consequence of mutations in the common c receptor

3. Cytokines and cytokine receptors: Basic concepts
A. Definitions:
A cytokine is a protein made by a cell, that when it binds to a cytokine receptor it exerts a biological effect.
Example: IFN- (gamma interferon)
Cytokines cause naïve T cells to differentiate into effector cells with specialized effector functions (Th1, Th2, Th17, Treg)
A lymphokine is a cytokine produced by a lymphocyte. An interleukin (IL) is a generic term used for many lymphokines: IL-2

4. Cytokines and cytokine receptors: Basic concepts
2. A chemokine is a special type of cytokine, known as a chemoattractant cytokine
CXCL8: recruits neutrophils from blood into tissues
Most cytokines are beneficial and act locally
However, cytokines can also have negative effects on the host:
dysregulated cytokine production can cause tissue damage
systemic cytokine production can cause death

5. Cytokines and cytokine receptors: Basic concepts
B. How do cytokines work?
Secretion
Binding to cytokine receptor
Activation of Jak-Stat pathway
Biological effect
1. Cytokines can be secreted in the following manner:
autocrine production: when the cell that secretes the cytokine is also the target cell
paracrine production: when the cytokine binds to a receptor that is expressed on a neighboring cell

6. Autocrine production

7. Paracrine production

8. Cytokines and cytokine receptors: Basic concepts
2. Cytokines bind to receptors with different structures:

9. Cytokines and cytokine receptors: Basic concepts
3. After a cytokine binds to a cytokine receptor, the JAK-STAT pathway is activated and leads to increased transcription of genes.
STAT: Signal Transducers and Activators of Transcription

10. II. Categories of cytokines important for the immune system
A. COMMON GAMMA CHAIN CYTOKINES (c)
IL-2 , IL-7, IL-15
Cytokine
Biological effects
IL-2
T cell growth
IL-7
T cell survival
IL-15
T cell survival, memory T cells
NK cell development

11. II. Categories of cytokines important for the immune system
Common gamma chain (c) cytokine receptor
All common gamma chain cytokines use the common c receptor
 X-linked severe combined immunodeficiency syndrome(X-SCID)
1. mutation in c
2. severe deficiency in T cells and NK cells, defective B cell responses (B cells cannot class switch properly)

12. II. Categories of cytokines important for the immune system
B. PRO-INFLAMMATORY CYTOKINES:
IL-12 family, interferons, TNF family
1. IL-12 family
 IL-12, IL-23, IL-27
 Products of macrophages and dendritic cells
 Effects of IL-12:
1. Stimulates secretion of IFN-
2. Induces the differentiation of T cells into IFN--producing Th1 cells
3. Immunity to intracellular pathogens (M. tuberculosis)

13. II. Categories of cytokines important for the immune system
IL-12 receptor:
Patients with IL-12 or IL-12R1 deficiencies are highly susceptible to Salmonella and Mycobacterial infections
How could a mutation in a cytokine receptor be more severe than a mutation in the cytokine that binds to that receptor?

14. II. Categories of cytokines important for the immune system
Interferons
IFN-, IFN-, IFN-
Originally called interferons because they interfered with viral replication. Double-stranded RNA is a potent inducer of IFN-. There are two types of interferons:
Type I interferons:
IFN-: produced by leukocytes, dendritic cells
IFN-: produced by fibroblasts

15. Effects of Type I interferons

16. II. Categories of cytokines important for the immune system
b. Type II interferons
IFN- (gamma interferon)
Produced by Th1 cells and NK cells
 Effects of IFN-:
activates macrophages
increased killing of intracellular pathogens
c. increased expression of MHC molecules
d. increased antigen presentation
e. promotes antibody class switching

17. II. Categories of cytokines important for the immune system
Hereditary IFN-R-deficiency
severe infections, death from intracellular bacterial infections

18. II. Categories of cytokines important for the immune system
3. Tumor Necrosis Factor (TNF) family
 TNF-, TNF- (lymphotoxin ), lymphotoxin , Fas-L, CD40 ligand
Cytokine
Biological effects
TNF-a
Activates neutrophils, macrophages
TNF-b (lymphotoxin-a)
Cytotoxicity
lymphotoxin-b
Lymph node development
Fas-L
Apoptosis

19. II. Categories of cytokines important for the immune system
Effects of TNF- production:
Local TNF-
stimulates IL-12 production, IL-12 induces IFN- production, IFN- activates macrophages, stimulates further TNF- production, containment of infection
Excessive local TNF-
autoimmune disease (rheumatoid arthritis)
Systemic TNF-
septic shock

20. II. Categories of cytokines important for the immune system
TNF receptor:
Mutations in Fas can cause defects in apoptosis (ie. ALPS)
Mutations in CD40L can lead to hyper IgM syndrome. Why?

21. II. Categories of cytokines important for the immune system
C. ANTI-INFLAMMATORY CYTOKINES
 Transforming growth factor  (TGF-, IL-10
 Effects of TGF-
1. Inhibits T cell proliferation
2. Inhibits inflammation
3. Regulatory T cells (Treg) can express TGF-
 Effects of IL-10:
Suppresses IL-12 production by macrophages
Inhibits T cell proliferation

22. III. Chemokine and chemokine receptors
Chemokines are chemoattractant cytokines. They are chemoattractant because they act as chemical signals to attract and recruit leukocytes from the blood into various tissues and organs.
How to recognize a chemokine
“L” = chemokine ligand
i. CXCL would be a chemokine
“R” = chemokine receptor
i. CXCR would be a chemokine receptor

23. III. Chemokine and chemokine receptors
Chemokine receptors are a class of 7-transmembrane, G-protein-coupled receptors
How do cytokine and chemokine receptors differ?

24. III. Chemokine and chemokine receptors
Important functions of chemokines:
1. Recruitment of lymphocytes into lymphoid tissues
2. Recruitment of cells from bone marrow to combat infection
3. Recruitment of cells into inflammatory sites
Chemokines are selective for the cells they recruit:
1. CXCL8: neutrophils
2. CCL2: monocytes
3. CCL11 eosinophils
4. CXCL13: B cells
5. XCL1: T cells

25. IV. Chemokines and chemokine receptors of clinical relevance
1. CXCL4
CXCL4-heparin complexes
cause autoimmune heparin-induced thrombocytopenia
2. CXCR4 and CCR5
HIV uses these receptors to infect cells
3. DARC (Duffy antigen receptor for chemokines)
Plasmodium (causative agent of malaria) uses DARC to infect cells
4. CXCL8
glomerulonephritis
5. CCL2 and CCL5
Recruit macrophages into atherosclerotic plaques