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