Cytokines

Lu Qing, PhD ， MDDepartment of Immunology

School of Medicin, Fudan UniversityTel ： 5423-7093

E-mail: fluqing@fudan.edu.cn

What are cytokines?

“Cytokines” are soluble protein secreted by the cells of innate and adaptive immunity and therefore mediate many of the functions of these cells

Based on their cellular sourcesmonokines (mononuclear phagocyte)lymphokines (lymphocytes)interlukins (leukocytes) (IL-1, IL-2, etc.)

A subfamily of cytokines primarily functions in directing migration of cells, these are called “chemotactic cytokines” or “chemokines”

Cytokines

General PropertiesFunctional Categories of CytokinesCytokine ReceptorsBiologic Actions

Cytokines

General PropertiesFunctional Categories of CytokinesCytokine ReceptorsBiologic Actions

Innate and adaptive Immunity

Phagocytes-identify, ingest, and destroy microbes

Mononuclear phagocytes

Neutrophils (polymorphonuclear leukocytes) Short-lived (6h);

the most abundant population of circulating WBCs;mediate the earliest phase of inflammatory response

Bacterium becomes attached to membrane evaginations called pseudopodia

Bacterium is ingested, forming phagosome

Phagosome fuses with lysosome

Lysosomal enzymes digest captured material

Digestion products are released from cell

(a)

(b)

NK cells-kill infected cells and tumor cells

perforin/granzyme (cytolysis) Fas/FasLTNF-/TNFR-I

Cell apoptosis

NK cells secret cytokine, mainly IFN-—to activate macrophage to destroy phagocytosed microbes.

Tumor necrosis factor (TNF) IL-1 IL-12Type I IFNs IL-15 IL-18

Mononuclear phagocytes are the principal source of cytokines of innate immunity

As a result of cellular activation:

Innate and adaptive Immunity

Repertoire of clones

Recognition of processed antigens:

peptide-MHC

ResponseClonal expansion

Functional differentiationMemory

Tolerance to self

Activation phaseTH1 （ IFN- ）TH2 （ IL-4,5, 13 ） TH17 （ IL-17 ） TR1 （ IL-10 ） Foxp3+Treg

CTL

Three elemental R‘s of T-cell biology: repertoire, recognition, response

Effector phase

Recognition phase

Cytokine production is one of the principal response of T cells to antigen recognition

T lymphocytes in response to Ags are the principal sources of cytokine in adaptive immunity .The function of T helper cells is mediated by cytokines

Cytokines are polypeptides produced by the cells of innate and adaptive immunity in response to microbes and other antigens as a result of cellular activation.

Cytokines initiate their actions by binding to specific membrane receptors on target cells.

The cellular responses to most cytokines consist of gene activation, resulting in the expression of new functions and sometimes the proliferation of the target cells

What are cytokines?

Cytokine actions may be local and systemic

Autocrineaction

Endocrine action

circulation

act at a distance from the site of infection

Paracrine action act on a nearby cell

act on cytokine-producing cell itself

T lymphocytes often secret cytokines at the site of contact with antigen-presenting cells .

Most cytokines act close to where they are produced

pleiotropismredundancysynergyantagonism

Cytokines

General PropertiesFunctional Categories of CytokinesCytokine ReceptorsBiologic Actions

Functional Categories of Cytokines

Mediators and regulators of innate immunityTumor necrosis factor (TNF), IL-1, IL-6, IL-12, Type I IFNs, IL-15, IL-18,chemokines

Mediators and regulators of adptive immunityIL-2, IL-4, IL-5, IFN-g, TGF-, LT(TNF- ), IL-13,etc

Stimulators of hematopoiesis granulocyte-CSF, G-CSF macrophage-CSF ， M － CSF granulocyte-macrophage-CSF, GM-CSF) erythropoietin, EPO TPO stem cell factor, SCF

Cytokines

General PropertiesFunctional Categories of CytokinesCytokine ReceptorsBiologic Actions

Cytokine Receptors

Type I cytokine receptorsType II cytokine receptors Ig superfamilyTNF receptorsSeven-transmembrane -helical receptors

*Classification of cytokine receptors based on structural homologies among the extracellular cytokine-binding domain.

-S-

S-

-S-

S-

-S-

S-

CC

C C

C1C3C2

C1C3C2

C1C3C2

C1C3C2

G protein

Ig superfamily

Type I cytokine-R

Type II cytokine-R

TNF-R Chemokine-R

IL-1 M-CSF C-kit

IL-2 IL-3 IL-4 IL-5 IL-6 IL-7

IL-9 IL-11 IL-12 IL-13 IL-15 OSM

GM-CSF

G-CSF EPO

IFN- IFN- IFN-IL-10

TNF- TNF- CD40L NGF FASL

IL-8 RANTES MIP-1 PF4

Cytokine receptor families and ligands

WSXWS

Conserved cycteins

–chain shared by IL-2 receptor family

IL-2R IL-4R IL-7R IL-9R IL-15R

common chain

Cytokine receptors consist of unique ligand-binding chains and one or more signal-transducing chains,which are often shared by receptors for different cytokines

Cytokine receptors and signaling

Different cytokines binding to cytokine receptors activated distinct signal transduction pathways resulting in gene activation.

Cytokines

General PropertiesFunctional Categories of CytokinesCytokine ReceptorsBiologic Actions

Biologic Actions

Cytokines That Mediate and Regulate Innate Immunity

Cytokines That Mediate and Regulate Adaptive Immunity

Cytokines That Stimulate Hematopoiesis

*Cytokines have many functions, we’ll focus on a few central functions of a few key cytokines

*Mononuclear phagocytes are the principal source of cytokines of innate immunity

Tumor necrosis factor (TNF) IL-1 IL-6chemokinesType I IFNs IL-12 IL-15 IL-18

Proinflammatory cytokines

Cytokines That Mediate and Regulate Innate Immunity

Active recruitment of the cells to the sites of infectionrecognition of microbes phagocytosis destruction

TNF

Low quantities(plasma conc.<10-9M)

Moderate quantities

High quantities(plasma conc.10-

7M)

Local inflammationSystemic effects Septic shock

Leukocyte

Activation

Adhesion molecule

Endothelial cell

IL-1,chemokines

FeverLow output

Hypoglycemia

Thrombus

*Mononuclear phagocytes are the principal source of cytokines of innate immunity

Tumor necrosis factor (TNF) IL-1 IL-6chemokines IL-12Type I IFNs IL-15 IL-18

Cytokines That Mediate and Regulate Innate Immunity

inflammation

BloodSecondary

lymphoid organs

Primary lymphoid organs

Tissue

directing migration of leukocytesChemokines

Physiologic traffic of lymphocytes through the organs

(1) inflammatory stimuli

(2) Constitutively produced in lymphoid organs

to inflammatory sites

Cellular sourcesCellular sources

Chemokine family and structure

The chemokines are classified into families based on the number and locationnumber and location of N-terminal of cyctein residues CXC 、 CC 、 C 、 CX3C

C: cycteinX: any amino acid

Family Structure

leukocytesendothelial cells epithelial cells fibroblasts

CXCL8/IL-8

CXCL4/PF4

CXCL1/GROα

CXCL10/IP-10

lymphocytes

Endothelial cells

neutrophils

CXC chemokines Microbesinflammatory

cytokines CCL2/MCP-1

CCL3/MIP-1

CCL5/RANTES

CCL11/Eotaxin

eosinophils

Mononuclear phagocytes

CC chemokines

basophilslymphocytes

The chemokine/chemokine-receptor family

Chemokines recruit the cells to sites of infection

Cytokines and Inflammation

Macrophages or DCs stimulated via microbes make pro-inflammatory cytokines, especially TNF (Tumor necrosis factor), IL-1, and IL-6

TNF and IL-1 signal to endothelial cells to make them:• Leaky to fluid (influx of plasma; containing antibodie

s, complement components, etc.)• Sticky for leukocytes, leading to influx of neutrophils

first, then monocytes, lymphocytesChemokines induce movement of leukocytes and their

migration toward chemical gradient of the cytokine

inflammation

BloodSecondary

lymphoid organs

Primary lymphoid organs

Tissue

directing migration of leukocytesChemokines

Physiologic traffic of lymphocytes through the organs

(1) inflammatory stimuli

(2) Constitutively produced in lymphoid organs

to inflammatory sites

Segregation of B cells and T cells in distinct areas of the lymph node is dependent on cytokines.

Chemokines regulate the traffic of lymphocytes and other cells through peripheral lymphoid tissues

CXCR5/CCR7

*Mononuclear phagocytes are the principal source of cytokines of innate immunity

Tumor necrosis factor (TNF) IL-1 IL-6chemokinesType I IFNs IL-12 IL-15 IL-18

Cytokines That Mediate and Regulate Innate Immunity

Type I IFNs

Major cellular sourcesIFN-: mononuclear phagocytes IFN-: fibroblasts

Potent stimulusviral infection

Functionmediate the early innate immune response to viral infections

Inhibits viral replication

Increase expression of class I MHC molecules

Stimulates the development of Th1 cells in human

type I IFN inhibits viral replication

virus

Viral replication

Induction of “antiviral state”

IFN-

Induction of enzymes that block viral replication

Potent stimulus

nucleus nucleus

Virus infected cells Nearby uninfected cell

*Mononuclear phagocytes are the principal source of cytokines of innate immunity

Tumor necrosis factor (TNF) IL-1 IL-6chemokinesType I IFNs IL-12 IL-15 IL-18

Cytokines That Mediate and Regulate Innate Immunity

Macrophage

Microbes

Activation

Dendriticcell

Antigen presentation

CD40 CD40LNaïve CD4+T cell

IL-12

TH1 cell

NK cell

IFN-

Macrophage activation;killing of phagocytosed microbes

CD8+ T cell

Killing of infected cell

Increased cytolytic activity

NK cell

Roles of cytokines in innate immunity and inflammation

0 1 3 6

Hours after LPS injection

Biologic Actions

Cytokines That Mediate and Regulate Innate Immunity

Cytokines That Mediate and Regulate Adaptive Immunity

Cytokines That Stimulate Hematopoiesis

Repertoire of clones

Recognition of processed antigens:

peptide-MHC

ResponseClonal expansion

Functional differentiationMemory

Tolerance to self

Activation phaseTH1 （ IFN- ）TH2 （ IL-4,5, 13 ） TH17 （ IL-17 ） TR1 （ IL-10 ） Foxp3+Treg

CTL

Three elemental R‘s of T-cell biology: repertoire, recognition, response

Effector phase

Recognition phase

Cytokine production is one of the principal response of T cells to antigen recognition

Function of T cell derived Cytokines

In the activation phase of T cell-dependant immune response:Regulate the growth and differentiation of various lymphocyte population

In the effector phase of adaptive immune response:Recruit, activate, and regulate specialized effector cells, such as mononuclear phagocytes, neutrophils, and eosinophils, to eliminate antigens

Cytokine of adaptive immunity are produced mainly by T lymphocytes in response to specific recognition of protein Ags.

The function of T helper cells is mediated by cytokines

Figure 8-20

IL-2

• a growth factor for antigen-stimulated T lymphocytes

• responsible for T cell clonal expansion after antigen recognition

Function of T cell derived Cytokines

In the activation phase of T cell-dependant immune response:Regulate the growth and differentiation of various lymphocyte population

In the effector phase of adaptive immune response:Recruit, activate, and regulate specialized effector cells, such as mononuclear phagocytes, neutrophils, and eosinophils, to eliminate antigens

Leukocyte recruitment (inflammation)

Neutrophil activation (killing of phagocytosed microbes)

IFN-: A principal macrophage-activating cytokine

IFN- treatment inhibits the propagation of Leishmania that survive within macrophages

• A more detailed introduction of functions of cytokines in adaptive immune response are in charpter 13 (Effector Mechanisms of Cell-Mediated Immunity)

Biologic Actions

Cytokines That Mediate and Regulate Innate Immunity

Cytokines That Mediate and Regulate Adaptive Immunity

Cytokines That Stimulate Hematopoiesis

Pluripotent stem cells

SCF and IL-7

In summary

• What are cytokines?• Cytokines that mediate innate immunity• Cytokines that mediate adaptive immunity• Cytokines That Stimulate Hematopoiesis

Colony stimulating factor, CSF

Cellular sources: Bone marrow stromal cells, leukocytesFunction: stimulate the growth and differentiation of immature leukocytesMembers: granulocyte-CSF, G-CSF macrophage-CSF ， M － CSF granulocyte-macrophage-CSF, GM-CSF) erythropoietin, EPO TPO stem cell factor, SCF

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