Symbiotic microbiota and the development of RORgt ... · Symbiotic microbiota and the development...
Transcript of Symbiotic microbiota and the development of RORgt ... · Symbiotic microbiota and the development...
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Symbiotic microbiota and the development
of RORgt-expressing cells
Lymphoid Tissue Development Unit
Gérard Eberl
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Self
~1012 cells ~ 104 genes The mammalian metabolome
The mammalian metabolome +
- Processing of nutrients
- Degradation of xenobiotics
- Protection from new microbes
- Regulation of epithelial homeostasis
The Superorganism
Optimal Fitness
Commensal
microbes
~1014 Bacteria
+ Archea
+ Fungi
+ Viruses
> 106 genes The microbial metabolome
+
The Host-Microbiota Superorganism
Eberl, Mucosal Immunology 2010
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Bacterial Flora
Weak Immunity
Equilibrium between the microbiota
and the host
Bacterial Penetration
Systemic infection
Strong Immunity
Bacterial Penetration
Inflammation I BD
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The host-microbiota equilibrium: robust homeostasis
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The host-microbiota equilibrium: robust homeostasis
The tool of the host: the immune system
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Mutualist Pathogen
Regulation Inflammation
MAMPs Ags
IL-2
IL-10
TGFb
...
IL-12
IL-23
TNF
…
Microbes
Immune
responses
Development of adaptive immunity
Lymphoid tissues
Lymphocyte subsets
Lymphocyte memory
G. Eberl, Mucosal Immunol 2010
The immune system to maintain homeostasis
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RORgt+ lymphoid cells
Fetus Newborn / Suckling Adult
LTi cells
NK22 cells
Th17 cells
Tg cells
iNKT cells
LNs, PPs Cryptopatches ILFs
Symbiotic microbiota
IL-22 Epithelial cells
IL-17, IL-22 Epithelial cells
IL-17 Neutrophils
+
Anti-microbial peptides
Y Y Y
Y
Y Y
Y Y
Y
IgA-producing B cells
Anti-microbial peptides
Neutrophils G. Eberl, Immunological Reviews, 2011
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Symbiotic bacteria of the human body
Clostridium
Bacillus
Lactobacillus
Enterococcus
(Listeria)
(Staphylococcus)
Bacteroides
Mycobacterium
Streptomyces
Bifidobacteriales
Escherichia
(Salmonella)
(Vibrio)
(Helicobacter)
(Bordetella)
(Neisseria)
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Adaptive and Innate lymphoid cells
T cells
Th1
Th2
Treg
Th17
Th22
ILCs
ILC1
ILC2
ILCreg
ILC3
ILC3
NK cells
Nuocytes
?
LTi cells
LTi cells
NK22 cells
IFNg
IL-4,5,6,13
TGFb, IL-10
IL-35
IL-17
IL-22
Cherrier et al., Curr. Opin. Immunol., 2012 bis
RORgt
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RORgt+ cells in the fetus: Lymphoid Tissue (LTi) cells
Cervical Mesenteric Cervical Mesenteric
Cervical Mesenteric Cervical Parathymic
RORgt ICAM-1 RORgt VCAM-1
E16.5
Eberl et al, Nat Immunol 2004
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CP iILF mILF
RORgt B220 CD11c Bouskra et al, Nature 2008
Eberl et al, Science 2004
RORgt
RORgt+ cells in the adult intestine: cryptopatch LTi cells
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Type 3 (RORgt+) ILCs
develop independently of microbiota
102
103
104
105
106
CD4+T
GFP+ LTi4 NK22
Nb
of
LP
L
SPF
GF
GFP+CD3-
Total Total
S. Sawa, Science 2010
days after birth
0
20
40
60
80
100
-28 -14 0 14 28 42 56
% i
n G
FP
+C
D3
-
C
D
NK22
LTi0
LTi4
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2 wk
8 wk
IL-22
0 10 2 10 3 10 4 10 5
0
20
40
60
80
100
74
0 10 2 10 3 10 4 10 5
0
20
40
60
80
100
47
0 10 2 10 3 10 4 10 5
0
20
40
60
80
100
38
0 10 2 10 3 10 4 10 5
0
20
40
60
80
100
29
LTi4 NKp46+ Il22
1
10
102
103
Rela
tiv
e g
en
e e
xp
ressio
ns
LT
i 4
LT
i 4
E15 2 wk 8 wk
LT
i 4
NK
p4
6+
NK
p46
+
*
*
Il-22 production by RORgt+ ILCs decreases with age
S. Sawa, Nat Immunol, 2011
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2 wk
0
1
2
3 43 3.6
LTi4 NKp46+
0 10 2
10 3
10 4
10 5
0 10 2
10 3
10 4
10 5
0 10 2
10 3
10 4
10 5
0
0.1
0.2
0.3
0.4
0
0 10 2
10 3
10 4
10 5
0
0.3
0.6
0.9
1.2
0
IL-17A
8 wk
Il17a
Rela
tiv
e g
en
e e
xp
ressio
ns
1
10
102
LT
i 4
LT
i 4
E15 2 wk 8 wk
LT
i 4
NK
p46
+
NK
p46
+
N.D
N.D
N.D
Il-17 production by RORgt+ ILCs decreases with age
S. Sawa, Nat Immunol, 2011
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Rela
tiv
e g
en
e e
xp
ressio
ns
Il22
SPF GF
RORgt+ILCs CD4+T
- + - +
1
NK
p46
+
LT
i 4
NK
p46
+
10
102
103
*
*
N.D
N.D
LT
i 4
SPF GF
*
*
NKp46+
LTi4
GF SPF
0 10 2 10 3 10 4 10 5
0
20
40
60
80
100
7
0 10 2 10 3 10 4 10 5
0
20
40
60
80
100
27
0 10 2 10 3 10 4 10 5
0
20
40
60
80
100
15
0
20
40
60
80
100
0 10 2 10 3 10 4 10 5
38
IL-22
Il-22 production by RORgt+ ILCs is repressed by microbiota
S. Sawa, Nat Immunol, 2011
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Development and function of RORgt+ innate lymphoid cells
days after birth -14 0 14 28 42 56
ckitlow
NK22
LTi0
LTi4
Lymph nodes
Peyer’s patches
Cryptopatches
ILFs
Epithelial
defense
Microbial
colonization
Clustered LTi4 and LTi0 cells
Effector P46 and Ckitlow cells
Pre-empt microbes
Epithelial cells IL-25 CPs/ILFs/B cells
IL-17/22
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The function of innate lymphoid cells
Cherrier et al., Curr. Opin. Immunol., 2012 bis
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CLP
IL-7R+ IL-7
HSC
4b7-
RORgtlo
4b7+
RORgt- NK Nuocyte
LTi NK22
Notch
Id2
Id2
Tox
RORgt
Id2
RORgt
Notch
AhR
B
T
Notch
IL-12
IL-15
IL-18
IL-25
IL-33 RORgt
AhR
IL-23
ROR Runx1
Tox
The development of ILCs
Cherrier et al., J. Exp.Med. 2012
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RORgt+ lymphoid cells
Fetus Newborn / Suckling Adult
LTi cells
NK22 cells
Th17 cells
Tregs
Tg cells
iNKT cells
LNs, PPs Cryptopatches ILFs
Symbiotic microbiota
IL-22 Epithelial cells
IL-17, IL-22 Epithelial cells
IL-17 Neutrophils
+
Anti-microbial peptides
Y Y Y
Y
Y Y
Y Y
Y
IgA-producing B cells
Anti-microbial peptides
Neutrophils G. Eberl, Immunological Reviews, 2011
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Lymphoid Tissue Development Unit
Sponsors
Excellence Team
Shinichiro SAWA Marie CHERRIER
Caspar OHNMACHT
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Gnotobiology Platform Marion Bérard
Christophe Brézillon
José Perez
Paroi bactérienne Ivo Gomperts-Boneca
Catherine Werts
Immunité Innée Jim Di Santo
Naoko Satoh-Takayama
CIGM Francina Langa
Nadine Cerf-Bensussan
Valérie Gaboriau-Routhiau
Daniel Cua
Mélanie Kleinschek