Asst.Prof.
Meroj A. Jasem
Ph.D. Student
Molecular Immunology Course
Baghdad 12/11/2018
TOLL like receptors
• Toll-like receptors (TLRs) are powerful molecular regulators by which the
immune system may “sense” the environment and protect the host from
pathogens or endogenous threats.
• In mammalian cells, several TLRs were identified with a tissue and cell type-
specific distribution.
Pattern Recognition Receptors
• Receptors on cell membrane and in the cytosol
• Recognizes PAMPs ,MAMPs and DAMPs
Pathogen-associated Molecular Patterns
• Specific to microorganisms or rather pathogen
• Required for survival of the microbe.
Microbe-associated Molecular Patterns
• Expressed by resident microbiota
Damage-associated Molecular Patterns
• Endogenous molecules derived by tissue damage
fibronectin, heparan sulphate, biglycan, fibrinogen, oligosaccharides of
hyaluronan, and hyaluronan breakdown
Genetic analysis of
early embryonic
development in the
fruitfly, Drosophila
(Nusslein-Volhard and
colleagues)
Toll-mutant drosophila are susceptible to
fungal infections
Toll: Origin of the word (1985)
• The researchers were so surprised that they spontaneously shouted
out in German "Das ist ja toll!" which translates as "That's great!".
[The Nobel Prize in Physiology or Medicine 1995: Christiane Nüsslein-
Volhard, Eric F. Wieschaus]
• The TLRs are germline-encoded transmembrane glycoproteins derived from a toll gene family, which
play a crucial role in the detection of many microbial patterns and activating the innate immune system.
• The expressions of TLRs are different in different types of white blood cells. They are expressed on
dendritic cells (DCs), macrophages, natural killer (NK) cells, T and B lymphocytes and non-immune
cells like epithelial cells, endothelial cells and fibroblasts.
• TLR ligands include PAMPs on infectious microorganisms, endogenous molecules and synthetic
agonists.
• There are at least 10 TLRs present in mammals each equipped with the unique ability to recognize
different PAMPs.
• Signals transduced through the TLRs cause synthesis and secretion of pro-infamatory cytokines and co-
stimulatory molecules, which promote infammatory responses that bring macrophages and neutrophils to
sites of inflammation.
• TLRs are type I membrane
glycoproteins.
• Extracellular region of TLRs
contains leucine-rich repeat (LRR)
motifs.
• The structure of the extracellular
domain of TLR3 was revealed by
crystallography studies as a large
horseshoe-shape
and a cytoplasmic tail that contains
a conserved region called the
Toll/IL-1 receptor (TIR) domain.
IL 1Rs contains three
immunoglobulin-like domains
• TLR1, TLR2, TLR4, TLR5, and TLR6 localized
on the cell surface and recognize microbial
membrane components.
• TLR3, TLR7, TLR8, and TLR9 expressed within
intracellular vesicles and recognize nucleic
acids.
• Intracellular vesicles with TLR3, TLR7, TLR8,
and TLR9 are localized in endoplasmic reticulum
(ER), endosomes, lysosomes, and
endolysosomes.
• Intracellular localization important for avoiding
contact with ‘‘self’’ nucleic acids and risk of
autoimmunity.
• Regulated mechanism is present for TLR
mobilization.
Different mammalian Toll-like receptors (TLRs) are specific
for different classes of microbial products
It is suggested that there are2 pathways
in TLR signaling
a MyD88 dependent pathway
(early)
a MyD88 independent pathway
(late)
TLRs and TIR Domain
myeloid differentiation primary response
gene and 88 refers to the number within
Cytoplasmic tails of TLRs show similarities to
a list of upregulated genes
IL-1 receptor (TIR)
Common adaptor to TLRs is MyD88
Crucial proline residue in all TLR TIR
domains, except TLR3
All TLRs likely have a MyD88 pathway (TLR3
is an exception)
TLR4 has a MyD88 independent pathway as Cytoplasmic
TIR domain
well
A more detailed look at the signaling pathway down-stream of
Toll-like Receptors (TLRs)
A more detailed look at the signaling pathway down-stream of
Toll-like Receptors (TLRs)
TLR4
Toll receptor interferon-β
MyD88 Knock out mice do not produce
inflammatory cytokines such as TNF-
However with TLR4 stimulation NF-B and JNK
delayed activity occurs
TLR3 stimulation also exhibits a MyD88
independent pathway
NFᴷB
Thank you
