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