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Symbiotic microbiota and the development
of the mammalian immune system
Lymphoid Tissue Development Unit
Gérard Eberl
Louis Pasteur
(1822-1895)
Robert Koch
(1843-1910)
Ilya Illitch Metchnikof (1845-1916)
Ilya Illitch Metchnikof (1845-1916)
Ilya Illitch Metchnikof (1845-1916)
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
Intestinal symbionts and defense
Nature 2008
Intestinal symbionts and defense
The host-microbiota equilibrium: robust homeostasis
The tool of the host: the immune system
Bacterial Flora
Weak Immunity
Equilibrium between the intestinal flora
and the immune system
Bacterial Penetration
Systemic infection
Strong Immunity
Bacterial Penetration
Inflammation I BD
Science 2008
Mutualist Pathogen
Regulation Inflammation
MAMPs Ags
IL-2
IL-10
TGF
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
ROR t+ lymphoid cells
Fetus Newborn / Suckling Adult
LTi cells
NK22 cells
Th17 cells
T 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
Symbiotic bacteria of the human body
Clostridium
Bacillus
Lactobacillus
Enterococcus
(Listeria)
(Staphylococcus)
Bacteroides
Mycobacterium
Streptomyces
Bifidobacteriales
Escherichia
(Salmonella)
(Vibrio)
(Helicobacter)
(Bordetella)
(Neisseria)
IL-17 in invertebrates
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
IFN
IL-4,5,6,13
TGF , IL-10
IL-35
IL-17
IL-22
Cherrier et al., Curr. Opin. Immunol., 2012 bis
ROR t
ROR t+ cells in the fetus: Lymphoid Tissue (LTi) cells
Cervical Mesenteric Cervical Mesenteric
Cervical Mesenteric Cervical Parathymic
ROR t ICAM-1 ROR t VCAM-1
E16.5
Eberl et al, Nat Immunol 2004
CP iILF mILF
RORgt B220 CD11c Bouskra et al, Nature 2008
Eberl et al, Science 2004
RORgt
ROR t+ cells in the adult intestine: cryptopatch LTi cells
IL-12
Cryptopatch
Bacterial Flora
-defensin 3
CCL20
–
TLRs
TLRs
TLRs
DCs
LTi cells
immature ILFs
+ B cells
IgA
–
TNF
mature ILFs
+
The CP/ILF system and intestinal homeostasis
NOD1 NOD1 NOD1 NOD1
NOD1
Bouskra et al, Nature 2008
Type 3 (ROR t+) 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
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 ROR t+ ILCs decreases with age
S. Sawa, Nat Immunol, 2011
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
p4
6+
N.D
N.D
N.D
Il-17 production by ROR t+ ILCs decreases with age
S. Sawa, Nat Immunol, 2011
Rela
tiv
e g
en
e e
xp
ressio
ns
Il22
SPF GF
ROR t+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 ROR t+ ILCs is repressed by microbiota
S. Sawa, Nat Immunol, 2011
Development and function of ROR t+ 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
Segmented Filamentous Bacteria (SFB)
SFBs are potent inducers of adaptive immunity
Valérie Gaboriau-Routhiau, Nadine Cerf-Bensussan, Immunity 2009
Bacteroides fragilis and PSA
Sarkis Mazmanian (CalTech)
Cell 2009
Lymphoid Tissue Development Unit
Sponsors
Excellence Team