T cellMacrophage Collaboration

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T cell/Macrophage Collaboration

• Penny Morel
• 3/31/08
• 4-0343, morel_at_pitt.edu

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Nature Rev. Immunol 323, 2003
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Functions of Macrophages

• Phagocytosis
• Removal of Ig-coated organisms (opsonization) or
  cells (ADCC)
• Kill pathogens (NO, superoxide production)
• Induce inflammation (secrete IL-1, IL-6, TNF-?)
• Activated macrophages are efficient killers of
  intracellular pathogens
• Effector cells in the Delayed Type
  Hypersensitivity (DTH) reaction

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IL-10 controls activated M?
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Classical activation of macrophages is mediated
by Th1 cells
Intracellular Bacteria, viruses
IFN-g
IL-12
DC
IL-2 IFN-g
IL-1 IL-6 TNF-?
IL-12
IFN-g
Mac-act
IgG2a (IgG1, IgG3)
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Positive TB skin tests
ve test in patient who was infected with TB 20
years previously
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Two interactions are important for classical M?
activation by Th1 cells

• CD40CD40L interaction between Th1 and M?
• IFN-? - secreted by Th1 and binding to IFN-?R on
  M?

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IFN-? increases ability of M? to present antigen
to T cells

• MHC class I expression increased by up-regulation
  of heavy chain, ?2m, TAP1, TAP2, LMP2, LMP7,
  MECL1 (proteosome subunits)
• MHC class II expression increased by
  up-regulation of ? and ? chains, invariant chain,
  HLA-DM. This is regulated by a single
  IFN-?-inducible gene CIITA (Class II
  transactivator)

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Annu. Rev. Immunol.19331, 2001
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IFN-? induces a respiratory burst

• iNOS and NO
• Reactive oxygen
• Hydrogen peroxide
• Heightened microbicidal state

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IFN-? induces expression of FcR on
M??????????????C?
FcR
Target cell
Mac
IgG
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Structure of IFN-? receptor
Annu. Rev. Immunol 15563, 1997.
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Annu. Rev. Immunol 15563, 1997.
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Annu. Rev. Immunol 15563, 1997.
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Annu. Rev. Immunol 15563, 1997.
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Chronic inflammation leads to disease

• Occurs if antigen persists
• Mycobacterium tuberculosis and other
  mycobacterial infections
• Granulotamous diseases
• Many autoimmune diseases are caused by Th1 cells

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Concise Pathology
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Histology of a granuloma
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IL-10-/- mice spontaneously develop inflammatory
bowel disease
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IL-10 -/- mice are more susceptible to lethal
septic shock
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Produce higher levels of TNF-a and IL-6 Infect.
Immun. 704441, 2002
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IL-4 and IL-13 induce alternative M? activation

• Down-modulate ROS and iNOS production
• Activates arginase pathway
• Down-modulate FcR expression
• Reduce cytokine production
• Increase MHC expression
• Alternative Mac activation - mannose receptor
  induction. Increase MHC class II

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Nature Rev. Immunol 323, 2003
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Nature Rev. Immunol.5953, 2005
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