Toll-like Receptors: role in innate
      and adaptive immunity

             Jay K. Kolls, M.D.
           Professor of P...
Figure 2-1
Figure 2-10
How do we innately sense
invading pathogens?
Hashimoto et. al. in Cell, 1998 cloned Toll which
is involved in dorsal-ventral embryonic polarity
Shared signaling pathwa...
Cloning of human Toll
The C3H/HeJ Mouse
(The End of the Beginning…)
          Resistant to LPS (and only LPS)
         (Heppner & Weiss, 1965)
 ...
The Mutation of Tlr4 in LPS-
Resistant C3H/HeJ Mice
                    CCT        CAT

                           X


   ...
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
Recruitment of MyD88,
          MAL/TIRAP          Lps2
  IRAK,
  IRAK-4
 TRAF-6                                IRF-3
 TAK...
TLR-4 deficient mice

C57BL/6   C3H/HeN              129/SvJ   C3H/HeJ




            104 CFU K. pneumoniae
             ...
Self Organizing Map Clustering:

 s                                  s
 i                                  i
 g           ...
5.0
      Hierarchical Clustering of all
                                                             4.0
       strains a...
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


                    108


               67         3
                     6

          53                  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
                                    IL-4              IL-4
                                               TH2...
Toll-dependent selection of microbial
antigens for presentation by dendritic cells.




 Nature. 2006
 Apr
 6;440(7085):8
...
Toll-dependent selection of microbial
antigens for presentation by dendritic cells.




Nature. 2006
Apr
6;440(7085):8
08-...
Toll-dependent selection of microbial
antigens for presentation by dendritic cells.




  Nature. 2006 Apr 6;440(7085):808...
Toll-dependent selection of microbial
antigens for presentation by dendritic cells.




  Nature. 2006 Apr 6;440(7085):808...
Toll-like Receptors: role in innate and adaptive immunity
Toll-like Receptors: role in innate and adaptive immunity
Toll-like Receptors: role in innate and adaptive immunity
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Toll-like Receptors: role in innate and adaptive immunity

  1. 1. Toll-like Receptors: role in innate and adaptive immunity Jay K. Kolls, M.D. Professor of Pediatrics Director, Division of Pediatric Pulmonology Laboratory of Lung Immunology and Host Defense Children's Hospital of Pittsburgh
  2. 2. Figure 2-1
  3. 3. Figure 2-10
  4. 4. How do we innately sense invading pathogens?
  5. 5. Hashimoto et. al. in Cell, 1998 cloned Toll which is involved in dorsal-ventral embryonic polarity Shared 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
  6. 6. Cloning of human Toll
  7. 7. 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 the Lps Locus (Watson, et al., 1978) LPS sensing depends upon a solitary receptor.
  8. 8. The Mutation of Tlr4 in LPS- Resistant C3H/HeJ Mice CCT CAT X P712H X Ecto Cyto
  9. 9. Genetic deletion of TLR4 leads to LPS hyporesponsiveness Hoshino K, et al J Immunol. 1999 Apr 1;162(7):3749-52.
  10. 10. Bug Detectors Nature 414, 701 - 703 (2001);
  11. 11. Figure 15-4 Toll/IL-1R homology domain (TIR domain)
  12. 12. Figure 15-5
  13. 13. Recruitment of MyD88, MAL/TIRAP Lps2 IRAK, IRAK-4 TRAF-6 IRF-3 TAK-1 MAPK, IKKβ Ifnβ Jnk, NOS IKKγ p38, IfnβR IκB PI3K NF-κB Stat-1 ? Genes (TNF, IL-1, IL-12, IL-6, etc).
  14. 14. TLR-4 deficient mice C57BL/6 C3H/HeN 129/SvJ C3H/HeJ 104 CFU K. pneumoniae i.t. Euthanized 0, 4, 16 hrs
  15. 15. Self Organizing Map Clustering: s s i i g g n n a a l l hours 0 4 16 0 4 16 hours 0 4 16 0 4 16 C3H/HeN C3H/HeJ C3H/HeN C3H/HeJ
  16. 16. 5.0 Hierarchical Clustering of all 4.0 strains at 0, 4 and 16 hrs: 3.0 2.5 C57 0 hours 2.0 129 0 hours 1.5 C3H/HeJ 0 hours E 1.2 x C3H/HeN 0 hours p r 129 4 hours e s 1.0 s ... C3H/HeJ 4 hours i 0.9 o C3H/HeN 4 hours n 0.8 0.7 C57 4 hours 0.6 C3H/HeJ 16 hours 0.5 C57 16 hours 0.4 129 16 hours 0.3 C3H/HeN 16 hours 0.2 0.1 0.0 Trust
  17. 17. TLRs and their Ligands Nature Immunology 2, 675 - 680 (2001)
  18. 18. Central role of TLR4 in the innate immune response to K. pneumoniae infection 5.0 4.0 3.0 2.5 C57BL/6 0 hours 2.0 129/SvJ 0 hours 1.5 C3H/HeJ 0 hours E 1.2 x C3H/HeN 0 hours p r 129/SvJ 4 hours e s 1.0 s ... C3H/HeJ 4 hours i 0.9 o C3H/HeN 4 hours n 0.8 0.7 C57BL/6 4 hours 0.6 C3H/HeJ 16 hours 0.5 C57BL/6 16 hours 0.4 129/SvJ 16 hours 0.3 C3H/HeN 16 hours 0.2 0.1 0.0 Trust
  19. 19. C57BL/6 108 67 3 6 53 29 4 C3H/HeN C3H/HeJ
  20. 20. TLR signaling: myD88 dependent and independent pathways
  21. 21. NOD proteins and innate immunity
  22. 22. Nod proteins activate caspase-I in the inflammasome
  23. 23. TLR signaling link innate and adaptive immunity
  24. 24. Th1 responses require signaling via MyD88 Nature Immunology 2, 947 - 950 (2001)
  25. 25. Th2 responses do not require Myd88 Nature Immunology 2, 947 - 950 (2001)
  26. 26. DC maturation to M. tb requires Myd88 Nature Immunology 2, 947 - 950 (2001)
  27. 27. IRAK-M is a negative regular of TLR signaling Cell. 2002 Jul 26;110(2):191-202
  28. 28. CD4+ T-cells IL-4 IL-4 TH2 IL-5 CD40 CD40L APC MHC CD4 x IL-10 Ag TCR T-cell B7.2 B7.1 CD28 CTLA4 x IL-2 IFN-γ TH1 IFN-γ TNF IL-12 IL-17A TH17 IL-6 TGF-beta, TNF IL-6, IL-23 IL-22
  29. 29. Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature. 2006 Apr 6;440(7085):8 08-12
  30. 30. Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature. 2006 Apr 6;440(7085):8 08-12
  31. 31. Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature. 2006 Apr 6;440(7085):808-12
  32. 32. Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature. 2006 Apr 6;440(7085):808-12
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