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Title: Cytokines, the intercellular messengers


1
Cytokines, the intercellular messengers
  • A cytokine-based approach to immunology
  • Prof. Pierre L. Masson

2
Cytokines Nature dislikes classification
IL-3,-7,-11
Interleukins (N gt 33) Monokines Lymphokines
3
The most important cytokines ? A difficult choice
because
Adhesion molecules
Redundancy same activity
TNF??and IL-1
?
Antagonism opposition
IFN-? ?
? IL-10
4
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
5
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.
6
Origins of naive lymphocytes
7
The lymph node
Parham P The Immune System Garland 2000
8
Gut-associated lymphoid tissue (GALT)
Brandtzaeg P. Pabst R. Trends Immunol. 200425570
9
The important role of MHC class I
Klein J and Sato A. N Engl J Med 2000343702
10
The important role of MHC class II
Klein J and Sato A. N Engl J Med 2000343702
11
The thymus tissue
AIRE, AutoImmune Regulator. Deficiency of this
transcription factor ? autoimmunity
Delves P and Roitt I. N Engl J Med 200034337-49
12
Antibodies are good to neutralise toxinsand
cytokines
13
Interactions T-B
Janeway CA et al. Immunobiology Garland, 2001
14
B-cell responses
15
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
16
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
17
Mechanism of Th1 response
Lekstrom-Himes JA, Gallin JI. N Engl J Med.
20003431703.
18
Macrophage activation to fight intracellular
pathogens (Th1)
Roitt I et al. Immunology, 7th ed. Mosby-Elsevier
2006
19
Cytokines patterns in leprosy lesions
Janeway CA et al. Immunobiology 5th ed. Garland,
2001
20
Epithelium activation is used to fight
extracellular bacteria (Th17)
Ye, P. et al. J. Exp. Med. 2001194519
21
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.

22
Suppressor T cells discovered in 1970
23
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.
24
How do we know what kind of response to make ?
25
Dendritic cell (DC) maturation
J Exp Med.2007 204 2245
26
The fates of naive TH cells are determined by DCs
MHC class I and II Cross-presentation
27
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.
28
Tissue microenvironments shape the function of DCs
TSLP IL-7-like cytokine preferentially
expressed by mucosal epithelial cells
29
Intestinal dendritic cells (DCs) enhance oral
tolerance
Viney JL, et al. J Immunol.19981605815.
30
DCs monitor the content of the intestinal lumen
by extending dendrites into the epithelium
Niess JH et al. Science.2005307254.
31
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.

32
Human tonsil
33
Human tonsillar epithelial cells
Liu YJ et al, Annu. Rev. Immunol. 2007. 25193
34
A plausible scenario for oral tolerance
35
In summary
36
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.
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