6: Innate Immune Receptors (TLRs)

how do innate immune receptors respond to PAMPs?

by initiating intracellular signaling cascades which lead to cytokine production (or phagocytosis)

what do innate immune receptors that bind to bacterial PAMPs often stimulate the production of?

inflammatory cytokines

what do innate immune receptors that bind to viral PAMPs stimulate the production of?

anti-viral cytokines

what do innate immune receptors recognize?

pathogen associated molecular pattern (PAMPs) on invading pathogens

how do innate immune receptors conserve genomic real estate?

by recognizing molecular patterns shared across broad classes of pathogens

which cells express virtually all innate receptors?

dendritic cell, monocyte, macrophage

which cells express some innate receptors?

T-cell, B-cell, natural killer cell

what does the structure of TLRs consist of?

• extracellular leucine-rich repeat region which binds to PAMPs

• transmembrane domain

• cytoplasmic signaling domain that interacts with adaptor molecules

what are the 3 steps of TLR signaling?

1. presence of ligand leads to TLR dimerization

2. adaptor proteins bind to cytosolic side of TLR dimer

3. cytokines are produced

what are the 2 types of pathways signaled by PRRs?

1. NF-κB pathway (inflammatory cytokines)

2. interferon pathway (antiviral cytokines)

what are the local effects upon activation of the NF-κB pathway (inflammatory cytokines)?

increased

• vascular permeability

• platelet aggregation

• immune cell recruitment

what are the systemic effects upon activation of the NF-κB pathway (inflammatory cytokines)?

increased

• neutrophil mobilization in bone marrow

• acute phase proteins in liver/adipose

• body temperature in CNS

what does activation of the interferon pathway (antiviral cytokines) lead to?

• interference with viral replication by initiating anti-viral gene expression

• recruitment and activation of natural killer cells

• increased MHC-I expression, peptide presentation, and lymphocyte recruitment

what is the PAMP for TLR-2?

lipoteichoic acid (LTA)

what is the PAMP for TLR-4?

lipopolysaccharides (LPS)

what is the PAMP for TLR-5?

flagellin

what is the PAMP for TLR-3?

dsRNA (viral)

what is the PAMP for TLR-7?

ssRNA (viral)

what is the PAMP for NOD-2?

muramyl dipeptide (found in intracellular gram-positive bacteria)

what is the PAMP for RIG-1 helicase?

viral RNA without a 5’ cap

which innate receptors lead to the stimulation of the NF-κB pathway and release of inflammatory cytokines?

• TLR-2

• TLR-4

• TLR-5

• NOD-2

which innate receptors lead to the stimulation of the interferon pathway and release of antiviral cytokines?

• TLR-3

• TLR-7

• RIG-1

what are the two antiviral cytokines released by the interferon pathway?

IFN-α and -β

what are the two inflammatory cytokines released by the NF-κB pathway?

interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α)

which 3 innate receptors lead to phagocytosis?

• formyl peptide receptor

• mannose receptor

• scavenger receptor