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Cytokines and Thelper subsets. MCB 150, Pr Coscoy. 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.

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i characteristics of cytokines cks
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
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.

T helper and




Effector T cell

Th cells control immune system through CKs.

activation of cells production of cytokines
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).
cytokine network on a local level
Cytokine Network on a Local Level

IL-4 Receptor


T cell

B cell

IL-2 gene

IL-4 gene

IL-2 Receptor


ii measuring cytokines
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.
iii actions of cytokines
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
Actions of Cytokines

IL-2 for

T-cell activation

T-cell help

for B cells

Inflammatory cytokines

iv properties of cytokines pleiotropy
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.
synergy experimental example
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






V. Functions

Of Cytokines

vi cd4 t helper subsets th1 th2 cytokine bias
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-g, TNF-bCKs 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 th2 original mouse experiments on th cells mosmann et al dnax 1986 j immunol
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-g, TNF-b
  • 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-g.)
th1 th2

Naïve Th0 IL-2, IL-4, IFN-g




Th2 cell

IL-4, IL-6, IL-10


Th1 cell

IL-2, IFN-g

th1 th2 antagonism il 4 blocks th1 ifn g blocks th2
Th1/Th2 AntagonismIL-4 blocks Th1 IFN-g blocks Th2





Th2 cell

IL-4, IL-6, IL-10

Th1 cell

IL-2, IFN-g

Th1/Th2 RegulationT-bet is a transcription factor that is required for Th1 specific genes such as IL-12Rb


Enhances T-bet

IL-4 blocks T-bet


Th2 cell

IL-4, IL-6, IL-10

Th1 cell

IL-2, IFN-g

il 4 vs ifn g
IL-4 vs IFN-g
  • T-bet (Th1 associated) activated by IFN-g and turned off by IL-4.
  • Conversely in Th2 transcription factor GATA-3 activated by IL-4 turned off by IFN-g.
role for th1 vs th2 in immune response
Role for Th1 vs Th2 in Immune Response
  • Both subsets activated in lymph nodes (LN) immune responses to complex antigens.
  • Th1 cells leave LN to find activated endothelium tissue to activate macrophages.
  • Th2 cells can stay in LN to activate B cells.
what controls th1 vs th2
What controls Th1 vs Th2?

1) Amount of antigen. Mouse experiments originally showed high dose for Th1.

2) MHC and TCR affinity.

High affinity TCR = Th1.

3) Dendritic cell subsets during activation.

APC subsets activate Th1 or Th2 preferentially.

4) Toll-like receptor activation.

influence of apc subsets on th1 th2 dendritic cell
Influence of APC Subsets on Th1/ Th2Dendritic cell
  • Myeloid-like dendritic cells produce abundant IL-12 and drive Th1.
  • Lymphoid-like dendritic cells produce low levels of IL-12 are permissive for Th2.
toll like receptors tlrs influence of apcs on th1 th2
Toll-like receptors (TLRs) Influence of APCs on Th1/ Th2
  • Evidence for TLR activation influencing Dendritic cell maturation.
    • TLR9 binds bacterial CpG DNA
    • TLR4 binding to bacterial heat shock proteins
  • TLR activation induces APC expression of IL-12, IL-23, IL-27 Th1
tlr vs il 12 in th1 th2 development
TLR vs IL-12 in Th1/ Th2 development
  • New evidence suggests that TLR activation influencing Th1 outcome through initiation of TLR adapter molecule MyD88.
  • May be more important than IL-12 for Th1.
myd88 mice fail to control acute toxoplasma infection
MyD88-/- mice fail to control acute Toxoplasma infection

Survival curve shows MyD88 is just as important as IL-12 for Th1 response after Toxoplasma infection.

Control mice ( ) MyD88-/- mice ( ) IL-12p40-/- mice ( )

Scanga et al The Journal of Immunology,

2002, 168: 5997-6001.

myd88 mice default to th2 role for tlr activation in th1 th2
MyD88-/- mice default to Th2 Role for TLR Activation in Th1/Th2

IFN-g IL-4 IL-5 IL-10 IL-13

A. MyD88-/- mice

Response to

Th2 pathogen

B. MyD88-/- mice

Response to

Th1 pathogen

C. WT mice

Response to

Th1 pathogen

th cytokine bias in disease examples
Th Cytokine Bias in DiseaseExamples

Leishmania in mice (Richard Locksley)

  • C57Bl.6 mice mice have Th1 immune response and resolve infection.
  • BALB/c mice produce Th2 cytokines unable to control Leishmania lesions.

Leprosy in Humans (Robert Modlin)

  • Tuberculoid form has Th1 response and limits disease (healing).
  • Lepromatous form has Th2 response and uncontrolled disease (leprosy).
th cytokine bias in disease leprosy skin disease caused by mycobacterium leprae
Th Cytokine Bias in Disease:LeprosySkin disease caused by Mycobacterium leprae

Tuberculoid: has Th1 response and limits disease (healing).

Lepromatous: has Th2 response and uncontrolled disease (leprosy).

cytokine bias in leprosy
Cytokine Bias in Leprosy

RNA from skin lesions of patients


Cytokines as Ligands







TNF-b or Lymphotoxin

LT a and b Receptors

Soluble or membrane bound

vii cytokine receptors
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 receptor families
Cytokine ReceptorFamilies

5 different families of receptors

based on common structural motifs.

--> see book for more details

il 2 receptor subfamily shared common g subunit
IL-2 Receptor SubfamilyShared common g subunit

Only IL-2 and IL-15 have unique alpha subunit

x linked scid common g chain deficiency
X-Linked SCID Common g chain Deficiency
  • Mutation in g chain so unable to signal through IL-2, IL-4, IL-7, IL-9, IL-15.
  • No T cells abnormal thymus.
  • Immunocompromised susceptible to infections.

SCID Patient with severe Candida in mouth.

gm csf receptor subfamily hematopoietin receptors
GM-CSF Receptor SubfamilyHematopoietin Receptors

Low affinity


compete for

common b subunit

to get high affinity



Granulocyte monocyte

Colony stimulating factor

gm csf receptor subfamily hematopoietin receptors39
GM-CSF Receptor SubfamilyHematopoietin Receptors

IL-3, IL-5




b subunit.

Cytokine Receptor Signal through JAKs and STATs

cytokine receptor signaling jaks and stats model of signal
Cytokine Receptor SignalingJAKs and STATs (Model of Signal)

Binding of cytokine ligand

brings together receptor subunits

JAKs (Janus Associated Kinases)

are tyrosine kinases that

phosphorylate tyrosines.

STAT (Signal Transducers and

Activators of Transcription )

dimerize for function.

jaks and stats usage by ck receptors
JAKs and STATsUsage by CK Receptors

Overlapping and Unique

JAK1 is commonly used

by CKs from completely

different CKR families

STAT6 is

ONLY used



The Yin and Yang

of Th1 and Th2

Immune Responses