1. Cytokines

2. Cytokines
Cytokines are soluble molecules that regulate the immune system.
Low molecular weight proteins with a short half life.
Produced by almost all cells of the innate and adaptive immune systems especially CD4+ T cells.
They facilitate communication between cells of the immune system in order to maintain homeostasis.
The also promote hypersensitivity and inflammatory responses and sometimes cause acute or chronic distress in tissue or organs.

3. Cytokines function by binding to receptors on target cells.

4. Three modes of cytokine action
Autocrine action - act on the same cell.
Paracrine action - act on nearby cells.
Endocrine action - function similar to hormone and act systemically.

5. Important properties of cytokines
Pleiotropic
Redundancy
Synergy
Antagonism
Cascade induction

6. Cytokine Receptors
Receptor expression is an important regulatory step in cytokine function.
There are several different receptor families
Generally, the receptor has two or three chains.
The α provides specificity for binding a particular ligand.
The β or γ chain facilitate signaling.
Several receptors can share the same β or γ chain
IL-2 receptor 6

7. Cytokines Most cytokines are produced by two types of cells
Macrophages: IL-1, IL-6 and TNFα
TH cells
TH1: IL-2, INFγ, TNFβ (lymphotoxin)
TH2: IL-4, IL-5, IL-10, and IL-13
Cytokines act in combination with each other which makes the system very complex.

8. Cytokines
Cytokines produced by lymphocytes are sometimes called lymphokines
Cytokines produced by monocytes and macrophages are sometimes called monokines
Cytokines that affect chemotaxis are called chemokines
Many cytokines are called interleukins

9. Macrophages Secrete: IL-1, IL-6, TNF-α Cytokine Function IL-1
Induces inflammation
Induces fever
Induction of acute phase protein synthesis
IL-6
Stimulates T cell activation
Stimulates B cell immunoglobulin production
Stimulates IL-2 production
TNF-α
Neutrophil activation

10. TH1 cells Secrete: IL-2, INFγ, TNFβ (lymphotoxin) Cytokine Function
T cell proliferation
NK activation and proliferation
INF-γ
Activates macrophages
Increases expression of MHC-I and MHC-II molecules
Increases antigen presentation
Inhibits TH2 cells
TNF-β
Inflammation
Plays a role in killing target cells by cytotoxic CD8 T cells

11. TH2 cells Secrete: IL-4, IL-5, IL-10, IL-13 Cytokine Function IL-4
B cell proliferation
TH2 proliferation
IgE synthesis
IL-5
B cell proliferation and secretion of antibodies
Eosinophil activation
IL-10
Inhibits TH1 production and macrophage function
IL-13

12. TH1 cells enhance cell mediated immunity
TH1 produce cytokines that enhance cell mediated cytotoxicity.
These cytokines include IL-2, INF-γ, Lymphotoxin (TNF-β, GM-CSF (granulocyte macrophage-colony stimulating factor) and IL-3.
They activate macrophages, Tc (cytotoxic cells before becoming effector cytotoxic T lymphocytes) and participate in DTH (delayed type hypersensitivity).
Cytokines from TH1 cells aid Tc cells development into CTLs (cytotoxic T lymphocytes)

13. TH2 cells enhance humoral immunity
TH2 produce cytokines that enhance humoral immune responses, allergic reactions and immune response against parasites
These cytokines aid B cells development into antibody-producing plasma cells.
Cytokines secreted by TH2 cells include IL-4, IL-5, IL-10, IL-13, IL-3 and GM-CSF.

15. TH1 and TH2 Cells
Once TH1 and TH2 get activated, the immune response is amplified through a cascade.
Activated TH1 and TH2 cells produce cytokines which trigger the production of more TH1 and TH2 cells.
TH1 and TH2 also down-regulate each other.
TH2 secrete IL-10 which inhibit TH1 response.
TH1 secrete IFN-γ which inhibit TH2 response.

17. CD8 cytotoxic T cells
Cytotoxic CD8 T cells act mainly through cytotoxins, but also produce cytokines that affect other cells of the immune system.

18. Cytotoxic CD8 T cells are selective and serial killers of target cells at sites of infection.
Following activation effector cytotoxic T cells (CTLs) begin making lytic granules–modified lysosomes containing a stored mixture of cytotoxins.
CTLs then migrate to areas of infection.
Recognition of specific peptide:MHC cause the CTL to:
Polarize, organizing its secretory apparatus toward the small localized area where the target cell it is attached to the CTL.
Release its lytic granules containing cytotoxins that induce the target cell to undergo apoptosis.

19. CD8 T Cell Destruction of Target Cells

20. CD8 T Cell Destruction of Target Cells
This specific targeting of lytic granules protects healthy neighbor cells and the CTL.
As the target cell begins to die the CTL:
Is released.
Begins making new lytic granules.
Moves on to kill another infected cell.

21. CD8 T Cell Destruction of Target Cells
Beside cytotoxins, CTLs also secrete the cytokine Interferon-g (IFN- g ) which:
Inhibits viral replication.
Increases processing and presentation of viral antigens by MHC class I.
Activates macrophages to get rid of dying cells.

22. Cytotoxic T cells kill their targets by inducing apoptosis.
Apoptosis or programmed cell death–cell suicide in which the cell shrivels and shrinks preventing the replication and release of intracellular pathogens.
The cell's own nucleases break down its DNA as well as the DNA of the intracellular pathogen.
The cell shrinks as the cytoplasmic membrane is given off in vesicles.
Changes in the cells cytoplasmic membrane target it for phagocytosis by macrophages which speeds the dying cell on its way.

23. Apoptosis versus Necrosis

24. Cytotoxic T cells induce apoptosis by two pathways:
1) Mediated by lytic granules –The cytotoxin perforin forms holes in the target cell through which a cytotoxin called granzyme gets inside and initiates apoptosis. 24

25. Cytotoxic T cells induce apoptosis by two pathways:
2) Mediated by cell surface molecules (Fas-ligand) on the membrane of the CTL
binds to Fas receptor on the target cell and initiates apoptosis.
Target cell
CD8 T cell

26. TH1 CD4 cells induce macrophages to become activated
TH1 cells act on macrophages, increasing their phagocytic ability and
capacity to kill ingested microbes
The enhancement of macrophage function is called macrophage activation 26

27. Macrophage Activation
Macrophage Activation – enhancement of macrophage function following interaction with TH1 CD4 T cells.
Macrophage activation results in:
Increased fusion of phagosomes with lysosomes (allowing killing of pathogens adapted to survive in phagosomes).
Increased production of the chemicals that break down pathogens in the lysosomes.
Increased expression of MHC class II and B7.

28. Macrophage Activation
Macrophage activation requires two signals from the TH1 CD4 T cells:
1) The cytokine IFN-g that is produced and released by the TH1 CD4 T cells
2) Interaction of CD40 ligand on the surface of the TH1 cell with CD40 receptor on the surface of the macrophage
CD8 T cells express IFN-g but not CD40 ligand so they can activate macrophages when bacterial polysaccharide is present which has a similar effect as CD40 ligand. 28

29. TH1 cells coordinate the host response to intravesicular pathogens.
Intravesicular pathogens (such as those that cause tuberculosis and leprosy) are sequestered in phagosomes where antibodies cannot get at them and they are not presented by MHC.
They also produce chemicals that inhibit their destruction in the phagolysosome.
TH1 cells coordinate the immune response:
By expressing a variety of molecules that result in an increase in the number of activated macrophages at the site of infection.
By expressing Fas ligand to induce apoptosis in the macrophage. 29

30. TH1 cells coordinate the host response to intravesicular pathogens.
If the above mechanisms are not successful an area of chronic inflammation called a granuloma can form.
The granuloma is composed of:
A central area of
Macrophages infected with resistant pathogens.
Multi-nucleated giant cells formed from the fusion of infected macrophages.
A covering of large individual macrophages that form an epithelium like layer around the center.
An outer layer of activated T cells. 30

31. Granuloma The center of the granuloma can become cut off
from the blood supply leading to the death of the
walled off cells in the center.
The granuloma results in a pathology, but it effectively prevents dissemination of the pathogen.

32. CD4 TH2 cells activate only those B cells that recognize the same antigen as they do
The T cell zone of secondary lymphoid tissue contain CD4 T cells that resulted from the rapid division of T cells activated by antigen presenting DCs.
The main function of these cells is to help B cells produce antibodies. 32

33. CD4 TH2 cells activate only those B cells that recognize the same antigen as they do
When a B cell presents specific antigen recognized by the CD4 TH2 cell:
Interactions between adhesion molecules are strengthened.
The B cell becomes trapped by the T cell.
The T cell expresses CD40 ligand and cytokines that induce the B cell to divide rapidly and differentiate into a plasma cell. 33

34. Cooperation occurs only between T and B cells that have cognate interactions
Cognate interactions – interactions in which the T and B cells share a specific antigen, although they usually recognize different epitopes.
Example:
Vaccine for Haemophilus influenza B (HIB) – the antigen that effective B cells recognize is a carbohydrate and T cells only recognize peptide antigens.
So the joining of the carbohydrate antigen to a protein antigen resulted in a single antigen that could be recognized by both T cells and B cells. 34

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36. Regulatory CD4 T cells limit the activities of effector CD4 and CD8 T cells.
Regulatory or Suppressor CD4 T cells – antigen specific T cells that inhibit immune responses.
These cells are identified by the expression of CD25.
They secrete cytokines that inhibit immune responses.
Their ability to suppress other T cells depends on physical contact with their target T cells. 36

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