Cytokines, the intercellular messengers

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Cytokines, the intercellular messengers

• A cytokine-based approach to immunology
• Prof. Pierre L. Masson

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Cytokines Nature dislikes classification
IL-3,-7,-11
Interleukins (N gt 33) Monokines Lymphokines
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The most important cytokines ? A difficult choice
because
Adhesion molecules
Redundancy same activity
TNF??and IL-1
?
Antagonism opposition
IFN-? ?
? IL-10
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We dont have three different modes of reaction
but at least five How do they work?

• Antibody
• Cytotoxicity
• Macrophage activation

4. Epithelium activation 5. Dampening the immune
reaction
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How do we know what kind of response to make ?
The nature of the response depends on the
pathogen but also on the affected organ or tissue
The cytokines released by the local cells
(epithelia, stromal cells) play a key role in
this selection.
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Origins of naive lymphocytes
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The lymph node
Parham P The Immune System Garland 2000
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Gut-associated lymphoid tissue (GALT)
Brandtzaeg P. Pabst R. Trends Immunol. 200425570
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The important role of MHC class I
Klein J and Sato A. N Engl J Med 2000343702
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The important role of MHC class II
Klein J and Sato A. N Engl J Med 2000343702
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The thymus tissue
AIRE, AutoImmune Regulator. Deficiency of this
transcription factor ? autoimmunity
Delves P and Roitt I. N Engl J Med 200034337-49
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Antibodies are good to neutralise toxinsand
cytokines
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Interactions T-B
Janeway CA et al. Immunobiology Garland, 2001
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B-cell responses
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Cytolytic T cells (CTLs) kill virally infected
cells and tumor cells

• Perforin forms a pore through which the granzymes
  are delivered in the cytosol.
• Apoptosis is triggered by
• granzymes,
• the interaction of CTL Fas ligand with target
  Fas,
• the secretion of TNF? ? and IFN-??
• Fas ligand is expressed by ocular and testicular
  tissues ? apoptosis of CTLs.

Parham P The Immune System Garland 2000
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Delves P and343108-117 Delves P and
Natural killer cells
NK cells are high producers of IFN-?
Delves P and Roitt I. N Engl J Med 200034337-49
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Mechanism of Th1 response
Lekstrom-Himes JA, Gallin JI. N Engl J Med.
20003431703.
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Macrophage activation to fight intracellular
pathogens (Th1)
Roitt I et al. Immunology, 7th ed. Mosby-Elsevier
2006
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Cytokines patterns in leprosy lesions
Janeway CA et al. Immunobiology 5th ed. Garland,
2001
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Epithelium activation is used to fight
extracellular bacteria (Th17)
Ye, P. et al. J. Exp. Med. 2001194519
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TH17 lymphocyte
TH17
IL-17 IL-22

• IL-23 shares p40 with IL-12.
• IL-17 is involved in various inflammatory
  diseases.
• IL-22 is responsible for psoriasis acanthosis.

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Suppressor T cells discovered in 1970
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Tranfer of Treg dampens inflammatory bowel
disease and autoimmune gastritis

• Natural Treg CD4
• Thymus
• Intercellular contact
• Induced Treg CD4
• Periphery
• Th3 ?TGF-?
• Tr1? IL-10
• Markers
• CD25 (a subunit of IL-2 receptor)
• Foxp3 (transcription factor)
• IL-7 receptor (CD127 is missing)
• CD39, enzyme ATP?adenosine
• Several cell types can be involved, e.g.
• T CD8, T??, NK-T, B-cells.
• Some viruses produce an IL-10-like cytokine.

Hori S, Nomura T, Sakaguchi S. Science.
20032991057.
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How do we know what kind of response to make ?
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Dendritic cell (DC) maturation
J Exp Med.2007 204 2245
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The fates of naive TH cells are determined by DCs
MHC class I and II Cross-presentation
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Activation of dendritic cells (DCs)
PAMPs, Pathogen-Associated Molecular Patterns
e.g. LPS, peptidoglycan, flagellin
DAMPs, Damage-Associated Molecular patterns
e.g.DNA and RNA, uric acid crystals
PRRs, Pattern Recognition Receptors, e.g.
Toll-like, scavenger, mannose-binding, etc.
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Tissue microenvironments shape the function of DCs
TSLP IL-7-like cytokine preferentially
expressed by mucosal epithelial cells
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Intestinal dendritic cells (DCs) enhance oral
tolerance
Viney JL, et al. J Immunol.19981605815.
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DCs monitor the content of the intestinal lumen
by extending dendrites into the epithelium
Niess JH et al. Science.2005307254.
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Induction of Treg in the gut

• IDO (indoleamine 2,3 dioxygenase) IDO is involved
  in tryptophan catabolism.
• IDO is inhibited by methyl-1 tryptophan.
• IDO contributes to fetomaternal and oral
  tolerance.
• IDO depresses the anti-tumor immune response.

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Human tonsil
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Human tonsillar epithelial cells
Liu YJ et al, Annu. Rev. Immunol. 2007. 25193
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A plausible scenario for oral tolerance
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In summary
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Do not forget !
The lymphoid system is connected to the
nervous and endocrine systems.
The next AIC session (Spring) will deal with
the effects of glucocorticoids on the immune
system.