pattern recognition receptors, the receptors of the innate

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