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
