Cytokines Lu Qing, PhD ， MD Department of Immunology School of Medicin, Fudan University Tel ：

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 sources monokines (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 Properties Functional Categories of Cytokines Cytokine Receptors Biologic Actions

Cytokines General Properties Functional Categories of Cytokines Cytokine Receptors Biologic 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/FasL TNF-  /TNFR-I Cell apoptosis

NK cells secret cytokine, mainly IFN-  —to activate macrophage to destroy phagocytosed microbes. Tumor necrosis factor (TNF) IL-1 IL-12 Type 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 Response Clonal expansion Functional differentiation Memory Tolerance to self Activation phase T H 1 （ IFN- ） T H 2 （ IL-4,5, 13 ） T H 17 （ IL-17 ） T R 1 （ IL-10 ） Foxp3 + T reg 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 Autocrine action 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

pleiotropism redundancy synergy antagonism

Cytokines General Properties Functional Categories of Cytokines Cytokine Receptors Biologic Actions

Functional Categories of Cytokines Mediators and regulators of innate immunity Tumor necrosis factor (TNF), IL-1, IL-6, IL-12, Type I IFNs, IL-15, IL-18,chemokines Mediators and regulators of adptive immunity IL-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 Properties Functional Categories of Cytokines Cytokine Receptors Biologic Actions

Cytokine Receptors Type I cytokine receptors Type II cytokine receptors Ig superfamily TNF receptors Seven-transmembrane  -helical receptors *Classification of cytokine receptors based on structural homologies among the extracellular cytokine-binding domain.

-S-S- C CC C CCC C C C1 C3 C2 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 Properties Functional Categories of Cytokines Cytokine Receptors 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-6 chemokines Type 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 infection  recognition of microbes  phagocytosis  destruction

TNF Low quantities (plasma conc.<10 -9 M) Moderate quantities High quantities (plasma conc.  M) Local inflammation Systemic effectsSeptic shock Leukocyte Activation Adhesion molecule Endothelial cell IL-1, chemokines Fever Low output Hypoglycemia Thrombus

*Mononuclear phagocytes are the principal source of cytokines of innate immunity Tumor necrosis factor (TNF) IL-1 IL-6 chemokines IL-12 Type I IFNs IL-15 IL-18 Cytokines That Mediate and Regulate Innate Immunity

inflammation Blood Secondary lymphoid organs Primary lymphoid organs Tissue directing migration of leukocytes Chemokines Physiologic traffic of lymphocytes through the organs (1) inflammatory stimuli (2) Constitutively produced in lymphoid organs to inflammatory sites Cellular sources

Chemokine family and structure number and location The chemokines are classified into families based on the number and location of N-terminal of cyctein residues CXC 、 CC 、 C 、 CX3C C: cyctein X: any amino acid Family Structure

leukocytes endothelial cells epithelial cells fibroblasts CXCL8/IL-8 CXCL4/PF4 CXCL1/GROα CXCL10/IP-10 lymphocytes Endothelial cells neutrophils CXC chemokines Microbes inflammatory cytokines CCL2/MCP-1 CCL3/MIP-1 CCL5/RANTES CCL11/Eotaxin eosinophils Mononuclear phagocytes CC chemokines basophils lymphocytes

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 antibodies, complement components, etc.) Sticky for leukocytes, leading to influx of neutrophils first, then monocytes, lymphocytes Chemokines induce movement of leukocytes and their migration toward chemical gradient of the cytokine

inflammation Blood Secondary lymphoid organs Primary lymphoid organs Tissue directing migration of leukocytes Chemokines 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-6 chemokines Type I IFNs IL-12 IL-15 IL-18 Cytokines That Mediate and Regulate Innate Immunity

Type I IFNs Major cellular sources IFN-  : mononuclear phagocytes IFN-  : fibroblasts Potent stimulus viral infection Function mediate 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 Virus infected cellsNearby uninfected cell

*Mononuclear phagocytes are the principal source of cytokines of innate immunity Tumor necrosis factor (TNF) IL-1 IL-6 chemokines Type I IFNs IL-12 IL-15 IL-18 Cytokines That Mediate and Regulate Innate Immunity

Macrophage Microbes Activation Dendritic cell Antigen presentation CD40 CD40LNaïve CD4+ T cell IL-12 T H 1 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 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 Response Clonal expansion Functional differentiation Memory Tolerance to self Activation phase T H 1 （ IFN- ） T H 2 （ IL-4,5, 13 ） T H 17 （ IL-17 ） T R 1 （ IL-10 ） Foxp3 + T reg 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, leukocytes Function: stimulate the growth and differentiation of immature leukocytes Members: granulocyte-CSF, G-CSF macrophage-CSF ， M － CSF granulocyte-macrophage-CSF, GM-CSF) erythropoietin, EPO TPO stem cell factor, SCF

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