Cytokines and Thelper subsets. I. Characteristics of Cytokines (CKs) CKs are small proteins (
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Transcript of Cytokines and Thelper subsets. I. Characteristics of Cytokines (CKs) CKs are small proteins (
Cytokines and Thelper subsets
I. Characteristics of Cytokines (CKs)
CKs are small proteins (<30 kDa) CKs are similar to hormones and growth
factors. CKs control the immune system.
Cytokines include subsets called lymphokines, monokines,
chemokines, etc.
Cytokine Network
CKs are part of complex system that regulates the immune system.
CKs are primarily produced by immune system but many other organs (liver, brain, endocrine glands) make CKs to influence immune response.
Cytokine Network
T helper and Macrophage Interactionhighlighted
Effector T cell
Th cells control immune system through CKs.
Activation of Cells = Production of Cytokines
Production of CKs is usually part of immune cell activation.
Cytokines are produced in response to different stimuli (e.g antigen receptor, cytokine/chemokine receptor).
T cell
IL-2
IL-2 gene
B cell
IL-2 Receptor
IL-4
Cytokine Network on a Local Level
IL-4 Receptor
IL-4 gene
II. Measuring Cytokines
Protein amount by ELISA. Good for in vitro experiments.
Protein amount by bioactivity assay using CK dependent cell lines.
RNA message by PCR.
Antigen Capture ELISA for IL-2
III. Actions of Cytokines
Autocrine acts on same cell that produced it. IL-2 for T cell activation
Paracrine acts on nearby cells. T cell help for B cells
Endocrine acts on cell at a distance (through bloodstream). Inflammatory cytokines.
Actions of Cytokines
IL-2 forT-cell activation
T-cell helpfor B cells
Inflammatory cytokines
IV. Properties of CytokinesPleiotropy
Same cytokine has different effects on cells can be activating or inhibiting.
Example: IL-10 can be inhibitory to macrophages and Th1 cells yet activating for Th2 cells and B cells.
SynergyExperimental Example
Proliferation of CTLLs(CTLLs are cytokine dependent cell line)
Both IL-2 or IL-4 activate CTLLs in vitro. Maximal proliferation obtained when both
IL-2 and IL-4 added. Both cytokines need to be blocked in order
to inhibit growth.
Properties of Cytokines
Pleiotropy
Redundancy
Synergy
Antagonism
CK Secreted Primary target Hallmark
IL-1 Macs,endothelium
Increases CAMsActivates macs
Pro-Inflammatory
IL-2 Th cells Th1, Tc, NK cells Th1 cytokine
IL-4 Th2 cells Th2 cells, B cells Th2 cytokine
IL-6 Macs Th2 cells Th2 cells, B cells ProInflam/Th2
IL-7 Bone marrow Stem cells Hematopoiesis
IL-8 Neutrophils Endothelial cells Chemokine
IL-10 Th2 cells, Macs, Th2 and B cells Th2 cytokine
IL-12 Macrophages,dendritic cells
Th1, Tc, NK cells Th1 cytokine
TNF- Macs, T, Bendothelial
tumor cells, macs,B cells, T cells
Pro-Inflammatory
TNF- Th1 cells macrophages, Th1cells,
Inflammatory
IFN-
Neutrophils,endo/epithelial
Uninfected cells Anti-viralcytokines
IFN Th1 cells,macrophages
macrophages, Th1 Th1 cytokineInflammatory
V. FunctionsOf Cytokines
VI. CD4+ T helper SubsetsTh1/Th2 Cytokine Bias
CD4+ Thelper cells can be divided into subsets based on their cytokine production.
Th1 cells produce IL-2, IFN-, TNF- CKs which activate cell mediated immunity
Th2 cells activate IL-4, IL-6, IL-10
CKs that activate humoral immunity These Th subsets were originally identified using mouse T cell clones.
Mouse Th Subset
Cytokine Th1 Th2
Table 12-4 from Goldsby
Th0 ---> Th1 or Th2Original mouse experiments on Th cells
(Mosmann et al (DNAX) 1986 J Immunol)
Antigen specific T cells placed in culture with antigen and APCs to make T cell lines.
Spleen cells (Th0) add IL-12 Th1 cells IL-2, IFN-, TNF-
Spleen cells (Th0) add IL-4 Th2 cells IL-4, IL-6,IL-10
(Th0 --precursor cell that produces IL-2, IL-4, and IFN-.)
Th1/Th2
Naïve Th0 IL-2, IL-4, IFN-
IL-4IL-12
EffectorTh1 cellIL-2, IFN-
EffectorTh2 cellIL-4, IL-6, IL-10
Th Cytokine Bias in Disease:LeprosySkin disease caused by Mycobacterium leprae
Lepromatous: has Th2 response and uncontrolled disease (leprosy).
Tuberculoid: has Th1 response and limits disease (healing).
Cytokines as Ligands
APCTarget
T Cell
TNF- or Lymphotoxin
Ligand
LT and Receptors Soluble or membrane bound
Receptor
VII. Cytokine Receptors
Expression of cytokine receptors controls the ability of a cytokine to act on a cell.
Cell activation increases cytokine receptor expression.
Cytokine ReceptorFamilies
5 different families of receptors based on common structural motifs. --> see book for more details
The Yin and Yang
of Th1 and Th2
Immune Responses