Cytokines and Immunoregulation

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Cytokines and Immunoregulation
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Cytokines

• Non-antibody proteins acting as mediators between
  cells
• Monokines produced by mononuclear phagocytes
• Lymphokines produced by activated lymphocytes,
  especially helper T cells
• Interleukins cytokines that act as mediators
  between leukocytes
• IL and a number

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Properties of Cytokines

• Produced by cells involved in both natural and
  adaptive immunity
• Mediate and regulate immune responses
• Secretion is limited
• Not store pre-formed
• Synthesis initiated by gene transcription and
  mRNA is short lived
• Produced as needed
• Can be produced by many cell types and act on
  many cell types (pleotropic)

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Properties of Cytokines

• Can have similar actions (redundant)
• Can share receptors
• Defect in a unique component can have little
  effect
• Defect in a shared component can have profound
  effects
• e.g. IL-2R? defect X-linked SCID

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Properties of Cytokines

• Can influence synthesis of other cytokines
• Cascades e.g. TNF ? IL-1 ? IL-6
• Enhance or suppress production of other cytokines
• Positive or negative effects on immune responses
• Can influence the action of other cytokines
• Antagonistic
• Additive
• Synergistic
• Bind to receptors with high affinity

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Properties of Cytokines

• Cell responding to the cytokine can be
• Same cell (autocrine)
• Nearby cell (paracrine)
• Distant cell (endocrine)
• Cellular responses to cytokines are slow (hrs)
• New mRNA and protein synthesis required

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Categories of Cytokines

• Mediators of natural immunity
• TNF-a
• IL-1
• IL-10
• IL-12
• Type I interferons (IFN-a, IFN-ß)
• IFN-?
• Chemokines

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Tumor Necrosis Factor (TNF-a)

• Produced by activated macrophages
• Most important mediator of acute inflammation in
  response to microbes, especially Gram- negative
  bacteria (LPS)
• Mediates recruitment of neutrophils and
  macrophages to site of inflammation by
  stimulating endothelial cells to produce adhesion
  molecules (e.g. ICAM-1)
• Stimulates endothelial cells and macrophages to
  produce chemokines
• Acts on hypothalamus to produce fever
• Promotes production of acute phase proteins

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Interleukin 1 (IL-1)

• Produced by activated macrophages
• Effects similar to TNF-a
• Helps activate T cells

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Interleukin 10 (IL-10)

• Produced by activated macrophages and Th2 cells
• An inhibitory cytokine
• Inhibits production of IFN-? by TH1 cells
• Shifts response to Th2 type
• Inhibits cytokine production by activated
  macrophages
• Inhibits expression of class II MHC and co-
  stimulatory molecules on macrophages

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Interleukin 12 (IL-12)

• Produced by activated macrophages and dendritic
  cells
• Stimulates production of IFN-?
• Induces differentiation of Th cells to become TH1
  cells
• Enhances cytolytic functions of T cells and NK
  cells

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Type I Interferons (IFN-a, IFN-ß)

• Produced by macrophages and many cell types
• Inhibit viral replication in cells
• Increase expression of class I MHC
• Activate NK cells

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Interferon Gamma (IFN-?)

• Produced by Th1 cells gtgtTc and NK cells
• Numerous function in both natural and adaptive
  immunity

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Chemokines

• Produced by many leukocytes and other cell types
• Large family of molecules (over 50)
• Chemotactic for leukocytes
• Recruit leukocytes to sites of infection
• Play a role in lymphocyte trafficking

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Categories of Cytokines

• Mediators of natural immunity
• Mediators of adaptive Immunity
• IL-2
• IL-4
• IL-5
• TGF-ß
• IL-10 (see above)
• IFN-? (see above)

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Interleukin 2 (IL-2)

• Produced by ThgtgtTc
• Main growth factor for T cells
• B cell growth factor
• NK cell activator
• Monocyte activator

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Autocrine Role of IL-2

• T Cell activation
• IL-2 secretion
• IL-2R expression
• Cell Division
• Receptor Decay

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Interleukin 4 (IL-4)

• Produced by macrophages and Th2 cells
• Stimulates development of TH2 cells from naïve Th
  cells
• Promotes growth of differentiated Th2 cells
• Stimulates Ig class switching to IgE isotype

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Interleukin 5 (IL-5)

• Produced by Th2 cells
• Promotes growth and differentiation of
  eosinophils
• Activates mature eosinophils
• Promotes B cell differentiation

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Transforming Growth Factor Beta (TGF-ß)

• Produced by T cells macrophages and other cell
  types
• Inhibits proliferation of T cells
• Inhibits activation of macrophages
• Acts on PMNs and endothelial cells to block the
  effects of pro-inflammatory cytokines

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Categories of Cytokines

• Mediators of natural immunity
• Mediators of adaptive immunity
• Stimulators of hematopoesis
• Granulocyte-macrophage colony stimulating factor
  (GM-CSF) promotes differentiation of bone marrow
  progenitors
• Macrophage colony stimulating factor (M-CSF)
  promotes growth and differentiation of monocytes
  and macrophages
• Granulocyte colony stimulating factor (G-CSF)
  promotes production of PMNs

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Cytokine Network

• Cytokines not only have effects on immune cells
  they also have effects on other cells and organ
  systems

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Regulation of Immune Responses

• Magnitude of an immure response is determined by
  antigen driven activation of lymphocytes and
  negative regulatory influences that prevent or
  dampen the response
• Regulatory mechanisms can act at the recognition,
  activation or effector phases of an immune
  response

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Regulation of Immune Responses

• Recognition of antigen in the absence of
  co-stimulation results in anergy (inability to
  respond)
• Recognition of antigen with CTLA-4 engagement of
  B7 results in down regulation of T cells
• Cytokines can have positive or negative effects
  on immune cell function
• Idiotype/anti-idiotype interactions can stimulate
  or inhibit antibody responses

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Regulation by Antibody

• Antibody competes with B cells for antigen

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Regulation by Antibody

• Antigen/Antibody complexes binding to Fc
  receptors sends an inhibitory signal to B cells.

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Regulation by Regulatory T cells (Tregs)

• Tregs do not prevent initial T cell activation,
  they inhibit a sustained response and prevent
  chronic and potentially damaging responses
• They do not have characteristics of Th1 or Th2
  cells
• They can suppress both Th1 and Th2 responses

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Regulation by Regulatory T cells (Tregs)

• Types of Tregs
• Naturally arising Treg
• Thymus gives rise to CD4CD25Foxp3 cells that
  function as Tregs
• CD25 is part of IL2 receptor
• Foxp3 is a transcription factor
• Defect leads to autoimmune and inflammatory
  disease
• Naturally arising Tregs suppress in a cell
  contact dependent manner
• Mechanisms not known

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Regulation by Regulatory T cells (Tregs)

• Types of Tregs
• Naturally arising Treg
• Induced Treg
• In the periphery some T cells are induced to
  become Tregs by antigen and IL-10 or TGF-ß
• IL-10 ? CD4CD25-Foxp3- (Tr1 cell)
• Suppress by secretion of IL-10
• TGF- ß ? CD4CD25Foxp3 (Induced Treg)
• Suppress by secretion of TGF- ß

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Regulation by Regulatory T cells (Tregs)

• Types of Tregs
• Naturally arising Treg
• Induced Treg
• CD8 Treg
• Induced by antigen and IL-10 in vitro
• In vivo ???
• Are CD8Foxp3
• Suppress by a cell contact dependent mechanisms
  or by secretion of cytokines