1. Cytokines
Non-antibody proteins acting as mediators between cells, termed:
Monokines – mononuclear phagocytes
Lymphokines – activated T cells, especially helper T cells
Interleukins – abbreviated IL with a number

2. Properties of Cytokines
Produced by cells involved in both natural and specific immunity
Mediate and regulate immune responses
Secretion brief and limited not stored pre-formed synthesis initiated by gene transcription - cytokines produced as needed

3. Properties of Cytokines (continued)
Can be produced by many cell types and act on many cell types (pleiotropic)
Can have similar actions (redundant)
IL2 Rα
IL2 Rβ
IL2 Rγ
IL15 Rα
IL7 R ?
IL9 R
IL4 R
IL-2
IL-15
IL-7
IL-9
IL-4
Receptor for:

4. Properties of Cytokines (continued)
6. Can influence synthesis of other cytokines
- produce cascades
- enhance or suppress production of other cytokines
- exert positive or negative regulatory mechanisms for immune responses
Influence action of other cytokines - can be antagonistic, additive, synergistic

5. Properties of Cytokines (continued)
Bind to receptors with high affinity
Cells responding to cytokine can be:
- same cell (autocrine)
- nearby cell (paracrine)
- distant cell by circulation (endocrine)
Cellular responses to cytokines are slow, require new mRNA and protein synthesis

6. Mediators and Regulators of Natural Immunity
Tumor Necrosis Factor-alpha (TNF-α)
Interleukin-1 (IL-1)
Chemokines (Chemotactic cytokines)
Type I Interferons (IFN-α and IFN-β)
Interleukin-12 (IL-12)
Interleukin-10 (IL-10)

7. Tumor Necrosis Factor (TNF-α)
Produced by activated macrophages
Most important mediator of acute inflammation in response to microbes, especially Gram-negative bacteria (LPS)
Mediates recruitment of neutrophils and macrophages to site of inflammation
Acts on hypothalamus to produce fever
Promotes production of acute phase proteins

8. Interleukin-1 (IL-1) Produced by activated macrophages
Effects similar to those of TNF-α

9. Chemokines Produced by many different leukocytes and tissue cells
Large family of >50 substances
Recruit leukocytes to sites of infection
Play a role in lymphocyte trafficking

10. Type I Interferons (IFN-α and β)
IFN-α a family of many proteins produced by macrophages, IFN-β a single protein produced by many cells
Both IFNs inhibit viral replication
Both increase expression of class I MHC
Both activate NK cells

11. Interleukin-12 (IL-12)
Produced by activated macrophages and dendritic cells
Stimulates production of IFN-γ
Induces differentiation of TH cells to become TH1 cells
Enhances cytolytic functions of cytotoxic T cells and NK cells

12. Interleukin-10 (IL-10) Produced by activated macrophages, TH2 cells
An inhibitory cytokine
Inhibits cytokine production by activated macrophages
Inhibits expression of class II MHC and costimulatory molecules on macrophages

13. Mediators and Regulators of Specific Immunity
Interleukin-2 (IL-2)
Interleukin-4 (IL-4)
Interleukin-5 (IL-5)
Interleukin-10 (IL-10)
Interferon-gamma (IFN-γ)

14. of division and IFN gamma release (and other mediators)
Interleukin-2 (IL-2)
Produced by TH>>Tc
Main growth factor for T cells
IL-2
secretion
T cell NK
Increase in NK
Cell activity
B cell
Stimulation
of division
of division and IFN gamma
release (and other mediators)
Monocyte
Activation

15. Autocrine Function of IL-2
Activated
T cell
Resting
Class II MHC
APC
IL2
IL4
IL7
Binds to IL-2 receptor
Receptor
decay
Division

16. Interleukin-4 (IL-4) Produced by TH2 cells
Stimulates Ig class switching to IgE isotype
Stimulates development of TH2 cells from naïve TH cells
Promotes growth of differentiated TH2 cells

17. Interleukin-5 (IL-5) Produced by TH2 cells
Promotes growth and differentiation of eosinophils
Activates mature eosinophils
IL-4 and IL-5 can work together Helminths opsonized with IgE can be killed by activated eosinophils

18. Interleukin-10 (IL-10) Produced by activated macrophages, TH2 cells
Inhibits production of IFN-γ by TH1 cells needed to activate macrophages

19. Interferon-gamma (IFN-γ)
Produced by TH cells >> Tc and NK cells
Numerous functions in both natural and specific immunity B
cell
Macrophage NK
T cell
TH1 cell >
Tc cell
Many cell types
Induction of class I
and class II MHC
Increase in NK
cell activity
Differentiation,
Stops cell division
T cell activation
Weak anti-viral activity,
Stops cell division,
Stops hematopoiesis
Activation
Granulocyte
Endothelial cell
IFN gamma
secretion

20. Stimulators of Hematopoiesis
Colony-Stimulating Factors (CSF)
Granulocyte-macrophage CSF (GM-CSF) promotes growth and differentiation of bone marrow progenitors
Macrophage CSF (M-CSF) is involved in development and function of monocytes and macrophages
Granulocyte CSF (G-CSF) stimulates production of polymorphonuclear leucocytes (PMN)

21. Cytokines Regulate Ig Class Switching
Fc region of antibodies determines effector function in different anatomical locations
Class (isotype) switching produces class or subclass of antibody most effective in host defense
Cytokines acting alone or in combination regulate class switching

22. Cytokine Network
Many cytokines have effects on many cells and organ systems in addition to functions in immune systems
Referred to as the “cytokine network”

23. Effects on Cells of Immune SystemNK
LAK
T cell B
cell
Activation of cells of immune system
Proliferation,
Differentiation,
Ig secretion and selection
Proliferation,
Differentiation,
Cytokine
production
Cytokine production
IL1 IL2 IL4
IL1 IL2 IL4 IL5 IL6 IFNγ
Macrophage
Lymphocyte
cytokines

24. Cytokine Effects on Organ Systems
Lymphocyte
Macrophage
Hypothalmus
ACTH
Adrenal gland
Corticosteroid
Liver
Acute phase proteins
Pituitary
IL1 IL6 TNF
Fever
-cortisol +DHEA
IL 6
cytokines

25. Cytokine Effects on Various Cells
Lymphocyte
Macrophage
Fibrogenesis
Extracellular matrix
cytokines
IL1 TNF
Endothelial cell
Fibroblasts
Fibrinogen
Permeability change
adhesion
Endothelial cells
TNF IL1 IFNγ
Hematopoiesis
Bone marrow
IL3 CSFs
Angiogenesis
Fibroblast
Extracellular
matrix
Osteoclasts
Tissue remodeling
Tissue repair
Anti-viral state
Many cell types
IL1 TNF IFNα IFNβ IFNγ

26. Complement functions Host benefit: Host detriment:
opsonization to enhance phagocytosis
phagocyte attraction and activation
lysis of bacteria and infected cells
regulation of antibody responses
clearance of immune complexes
clearance of apoptotic cells
Host detriment:
Inflammation, anaphylaxis

27. Pathways of complement activation
CLASSICAL
PATHWAY
LECTIN
PATHWAY
ALTERNATIVE
PATHWAY
antibody
dependent
antibody
independent
Activation of C3 and
generation of C5 convertase
activation
of C5
LYTIC ATTACK
PATHWAY

28. Complement Activation
Digestion in lysosome
Bacteria in plasma
Complement
activation
Lysis and
ingestion

29. Monocytes Macrophages Fibroblasts Epithelial cells Endothelial cells
FEATURES OF CYTOKINES
Cytokine
Cell Source
Cell Target
Primary Effects
IL-1
Monocytes  Macrophages Fibroblasts Epithelial cells Endothelial cells
T cells; B cells Endothelial cells Hypothalamus Liver
Costimulatory molecule Activation (inflammation) Fever Acute phase reactants
IL-2
T cells; NK cells
T cells B cells Monocytes
Growth Growth Activation
IL-3
T cells
Bone marrow progenitors
Growth and differentiation
IL-4
Naive T cells T cells B cells
Differentiation into a TH 2 cell Growth Activation and growth; Isotype switching to IgE
IL-5
B cells Eosinophils
Growth and activation
IL-6
T cells; Macrophages; Fibroblasts
T cells; B cells Mature B cells Liver
Costimulatory molecule Growth (in humans) Acute phase reactants
IL-8 family
Macrophages; Epithelial cells; Platelets
Neutrophils
Activation and chemotaxis
IL-10
T cells (TH2)
Macrophages T cells
Inhibits APC activity Inhibits cytokine production
IL-12
Macrophages; NK cells
Naive T cells
Differentiation into a TH 1 cell
IFN-gamma
Monocytes Endothelial cells Many tissue cells -  especially macrophages
Activation Activation Increased class I and II MHC
TGF-beta
T cells; Macrophages
T cells Macrophages
Inhibits activation and growth Inhibits activation
GM-CSF
T cells; Macrophages; Endothelial cells, Fibroblasts
TNF-alpha
Macrophages; T-cells
Similar to IL-1
IL = interleukin GM-CSF = granulocyte-macrophage colony stimulating factor IFN = interferon TNF = tumor necrosis factor TGF = transforming growth factor