pattern recognition receptors, the receptors of the innate
TRANSCRIPT
Pattern recognition receptors, the receptors of the Innate Immunity
Binfeng Lu, Ph.D.Department of Immunology
University of Pittsburgh School of Medicine
Bacterial Cell Walls
Virus
Figure 2-10
How do we innately sense invading pathogens?
• Hashimoto et. al. in Cell, 1988 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, capable of inducing NF-kB, leading to the production of inflammatory cytokines: IL-1, and IL-6 and co-stimulatory molecule B7.1. (Medzhitov R et al Nature 1997)
Belvin et al Annual Review of Cell and Developmental Biology 1996
Belvin et al Annual Review of Cell and Developmental Biology 1996
Anti-fungal
Anti-bac
Toll pathway in drosophila
Cloning of human Toll
Medzhitov R et al Nature 1997
Subfamilies of TLRs
Takeda et al Annu Rev Immunol 2003
The C3H/HeJ MouseThe C3H/HeJ Mouse
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)
The Mutation of Tlr4 in LPS-Resistant C3H/HeJ Mice
The Mutation of Tlr4 in LPS-Resistant C3H/HeJ Mice
X
CCT CAT
P712H
X
Ecto CytoQureshi et al J Exp Med. 1999 Feb 15;189(4):615-25.Poltorak et al Science, 1998
Genetic deletion of TLR4 leads to LPS hyporesponsiveness
Hoshino K, et al
J Immunol. 1999 Apr 1;162(7):3749-52.
Finding TLR ligands
Hayashi et al 2001 Nature 410:1099–10
Drosophila bug detectors
Akira et al Cell 2006
ss RNA
TLR complex and their Ligands
Nature Immunology 2, 675 - 680 (2001). TLR1 is also involved in lipopeptide recognition
CD14
TLR structure
Copyright ©2005 by the National Academy of Sciences
Bell, Jessica K. et al. (2005) Proc. Natl. Acad. Sci. USA 102, 10976-10980
Fig. 1. Overview of TLR3-ECD structure
Copyright ©2005 by the National Academy of Sciences
Fig. 3. Proposed modes of ligand recognition for TLR3-ECD
Choe, J., Kelker, M.S., Wilson, I.A. Crystal structure of human toll-like receptor 3 (TLR3) ectodomain. Science 309, 581-5 (2005).
TIR domain
Myd88
http://www.icampus.ucl.ac.be/courses/SBIM2520/document/genemol/pictures/TRLsignaling.html
Myd88 independent
Oshiumi et al Nat Immunol. 2003
Kawai T, Akira S. Cell Death Differ. 2006
TLR signaling: myD88 dependent and independent pathways
IRAK-M is a negative regular of TLR signaling
Cell. 2002 Jul 26;110(2):191-202
TLR expression on human PBMCs
J Immunol. 2002 May 1;168(9):4531-7.
Epithelial cells
NOD proteins and innate immunity
Nod proteins activate caspase-I in the inflammasome
Akira et al Cell 2006
Akira et al Cell 2006
TH2IL-4
IL-5
IL-10
TH1
IL-2
IFN-
TNF
IL-12IL-12
IFN-IFN-
IL-4IL-4
x
x
TGF-beta, TGF-beta, IL-6, IL-23IL-6, IL-23
TH17
IL-17A
IL-6
TNF
IL-22
TLR signaling link innate and adaptive immunity
APC
CD40
AgMHC
B7.2B7.1
T-cell
CD40L
TCRCD4
CTLA4CD28
APC
CD40
AgMHC
B7.2B7.1
T-cellT-cell
CD40L
TCRCD4
CTLA4CD28
Th1 responses require signaling via MyD88
Nature Immunology 2, 947 - 950 (2001)
Th2 responses do not require Myd88
Nature Immunology 2, 947 - 950 (2001)
TLRS in Human Disease
• Nod2 mutations in Chron’s Disease• Unc93b – “3d” mutation
– TLR3, 7, 9
TLRS in Human Disease
Cook et al. Nature Immunology 5, 975 - 979 (2004)
TLR and autoimmunity
• TLR and lupus development