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Toll-like Receptors: role in innate and adaptive immunity
Jay K. Kolls, M.D.Jay K. Kolls, M.D.Professor of PediatricsProfessor of Pediatrics
Director, Division of Pediatric Director, Division of Pediatric PulmonologyPulmonology
Laboratory of Lung Immunology and Host Laboratory of Lung Immunology and Host DefenseDefense
Children's Hospital of PittsburghChildren's Hospital of Pittsburgh
Figure 2-1
Figure 2-10
How do we innately sense invading pathogens?
Hashimoto et. al. in Cell, 1998 cloned Toll which Hashimoto et. al. in Cell, 1998 cloned Toll which is involved in dorsalis involved in dorsal--ventral embryonic polarityventral embryonic polarityShared signaling pathways between Toll and NF-kB suggested an immune function of Toll which was showed by the requirement for Toll to produce the anti-fungal peptide dorsomycin in Drosophila (Lemaitre, B. et. al. Cell, 1996).Medzhitov et. al. cloned human Toll, a type I transmembrane protein (amino terminus outside the cell) capable of inducing NF-kB, IL-1, and IL-6 and is expressed in the spleen and PBLs
Cloning of human Toll
The C3H/HeJ Mouse(The End of the Beginning…)The C3H/HeJ Mouse(The End of the Beginning…)
Resistant to LPS (and only LPS)(Heppner & Weiss, 1965)
Hypersusceptible to Authentic G(-)Infections (O’brien, 1980; Svanborg, 1983)
Codominant mutation of theLps Locus (Watson, et al., 1978)
Resistant to LPS (and only LPS)(Heppner & Weiss, 1965)
Hypersusceptible to Authentic G(-)Infections (O’brien, 1980; Svanborg, 1983)
Codominant mutation of theLps Locus (Watson, et al., 1978)
LPS sensing depends upon a solitary receptor.
The Mutation of Tlr4 in LPS-Resistant C3H/HeJ MiceThe Mutation of Tlr4 in LPS-Resistant C3H/HeJ Mice
X
CCT CAT
P712HX
Ecto Cyto
Genetic deletion of TLR4 leads to LPS hyporesponsiveness
Hoshino K, et al
J Immunol. 1999 Apr 1;162(7):3749-52.
Bug Detectors
Nature 414, 701 - 703 (2001);
Figure 15-4
Toll/IL-1R homology domain (TIR domain)
Figure 15-5
IRAK,
TRAF-6TAK-1
IκBNF-κB
Genes (TNF, IL-1, IL-12, IL-6, etc).
MAL/TIRAP
IRAK-4
MAPK,Jnk,p38,PI3K
IKKβIKKγ
Recruitment of MyD88,Lps2
IRF-3
IfnβNOS
Stat-1Stat-1IfnβRIfnβR
??
101044 CFU CFU K. pneumoniae K. pneumoniae i.t.i.t.
Euthanized 0, 4, 16 hrsEuthanized 0, 4, 16 hrs
C57BL/6C57BL/6 129/SvJ129/SvJC3H/HeN C3H/HeJ
TLR-4 deficient mice
C3H/HeNC3H/HeN C3H/HeJC3H/HeJ
hourshours 0 4 16 0 4 16 0 4 16 0 4 160 4 16 0 4 16hourshours
C3H/HeNC3H/HeN
Self Organizing Map Clustering:Self Organizing Map Clustering:
C3H/HeJC3H/HeJ
ssiiggnnaall
ssiiggnnaall
C57 0 hours
129 0 hours
C3H/HeJ 0 hours
C3H/HeN 0 hours
129 4 hours
C3H/HeJ 4 hours
C3H/HeN 4 hours
C57 4 hours
C3H/HeJ 16 hours
C57 16 hours
129 16 hours
C3H/HeN 16 hours
...
0.0
0.1
0.2
0.3
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0.5
0.6
0.7
0.8
0.9
1.0
1.2
1.5
2.0
2.5
3.0
4.0
5.0
Expression
Trust
Hierarchical Clustering of all strains at 0, 4 and 16 hrs:
TLRs and their Ligands
Nature Immunology 2, 675 - 680 (2001)
Central role of TLR4 in the innate immune response to K. pneumoniae infection
C57BL/6 0 hours
129/SvJ 0 hours
C3H/HeJ 0 hours
C3H/HeN 0 hours
129/SvJ 4 hours
C3H/HeJ 4 hours
C3H/HeN 4 hours
C57BL/6 4 hours
C3H/HeJ 16 hours
C57BL/6 16 hours
129/SvJ 16 hours
C3H/HeN 16 hours
...
C57BL/6 0 hours
129/SvJ 0 hours
C3H/HeJ 0 hours
C3H/HeN 0 hours
129/SvJ 4 hours
C3H/HeJ 4 hours
C3H/HeN 4 hours
C57BL/6 4 hours
C3H/HeJ 16 hours
C57BL/6 16 hours
129/SvJ 16 hours
C3H/HeN 16 hours
...
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.2
1.5
2.0
2.5
3.0
4.0
5.0
Expression
Trust0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.2
1.5
2.0
2.5
3.0
4.0
5.0
Expression
Trust
C57BL/6
C3H/HeJC3H/HeN
108
67 36
453 29
TLR signaling: myD88 dependent and independent pathways
NOD proteins and innate immunity
Nod proteins activate caspase-I in the inflammasome
TLR signaling link innate and adaptive immunity
Th1 responses require signaling via MyD88
Nature Immunology 2, 947 - 950 (2001)
Th2 responses do not require Myd88
Nature Immunology 2, 947 - 950 (2001)
DC maturation to M. tb requires Myd88
Nature Immunology 2, 947 - 950 (2001)
IRAK-M is a negative regular of TLR signaling
Cell. 2002 Jul 26;110(2):191-202
CD4+ T-cells
APC
CD40
AgMHC
B7.2B7.1
T-cell
CD40L
TCRCD4
CTLA4CD28
APC
CD40
AgMHC
B7.2B7.1
T-cellT-cell
CD40L
TCRCD4
CTLA4CD28
TH2IL-4
IL-5
IL-10
TH1
IL-2
IFN-γ
TNFILIL--1212
IFNIFN--γγ
ILIL--44
x
x
TGFTGF--beta, beta, ILIL--6, IL6, IL--2323
TH17
IL-17A
IL-6
TNF
IL-22
Toll-dependent selection of microbial antigens for presentation by dendritic cells.
Nature. 2006 Apr 6;440(7085):808-12
Toll-dependent selection of microbial antigens for presentation by dendritic cells.
Nature. 2006 Apr 6;440(7085):808-12
Toll-dependent selection of microbial antigens for presentation by dendritic cells.
Nature. 2006 Apr 6;440(7085):808-12
Toll-dependent selection of microbial antigens for presentation by dendritic cells.
Nature. 2006 Apr 6;440(7085):808-12
