Innate Immunity Receptors

Define how pattern recognition receptors function during an innate immune response

As mentioned in my first Immunology post, the innate immune system acts early, but non-specifically. That's not to say that there aren't any specific things that the innate system looks out for, however. There are a wide range of molecules that can be detected by receptors on cells involved in the innate immune response.

The main types of molecules that are detected by these receptors are called PAMPs and DAMPs. PAMPs are "pathogen-associated molecular patterns" and include some of the features that are common to microbes (but not to humans), such as lipopolysaccharide on the cell walls of gram-negative bacteria. DAMPs are "danger-associated molecular patterns" and are molecules that generally have some kind of usual function when they're within a healthy, functioning cell, but are released from infected or damaged cells.

So what are these receptors exactly? Broadly speaking, they are known as Pattern Recognition Receptors (PRR), and are expressed by many cells of the body (not just immune cells). These receptors are activated when bound, causing a cascade of other signals to happen. There are several different types of PRRs, as you shall see...

Describe features of different innate immune receptors

Toll-like receptors

Toll-like receptors (TLRs) are located on the surface as well as inside cells, and are able to recognise DAMPs and PAMPs. They are generally anchored to a membrane of some sort. On one side of the membrane they have a horse-shoe structure made of leucine-rich repeats (LRR) which assists in ligand binding. On the other side they have an intracellular cytoplasmic tail, which assists in signal transduction. They sometimes form homodimers or heterodimers.

Now it's time to look at a select few in a bit more detail!

TLR4 is located on the cell membrane and recognises lipopolysaccharide (LPS), which as I mentioned earlier is a component of Gram-negative bacteria cell walls. In order to do so, however, it requires some help from a couple of other proteins: CD14, which binds LPS and brings it to TLR4, and LPS-binding protein, which stabilises the interactions between LPS and TLR4. The cytoplasmic tail of TLR4 is associated with MyD88, which is an adaptor protein. Adaptor proteins are proteins that dock signalling proteins so that they're all nice and close and ready to signal. In the case of TLR4, signalling occurs via the NFκB pathway, which induces transcription of inflammatory cytokine genes. This ultimately results in cytokine expression, as well as expression of some cell surface molecules (such as CD80 and CD86) which are required for antigen presentation.

TLR7 is usually located in the nucleus or cytoplasm, but during infection with an ssRNA virus, it is located on the membranes of endosomes. Endosomes are the little bubbles that are made when things are endocytosed. In this case, it's the ssRNA virus that's being engulfed in the endosome. This exposes the ssRNA genome of the virus so that it can bind to TLR7. Ultimately, this leads to expression of Type I Interferon (IFN), which as I mentioned here, is not good from the virus' point of view.

Expression of IFN isn't the end of the game for a virus, however. While IFN can induce signalling pathways producing products that block virus replication and propagation, the virus can block the production of these products or even production of IFN itself. Rude.

NOD-like receptors

NOD-like receptors (NLRs) are so-called because they contain a nucleotide-binding oligomerisation domain, or NOD. That's a bit of a mouthful, but all you really need to know is that they're located in the cytoplasm and detect breakdown products of peptidoglycans, which are components of bacterial cell walls. Just like TLR4, NLRs can induce the activation of NFκB. (One thing to remember is that of the receptors in this post, those that target bacterial components induce NFκB activation, while those that target viral components induce IFN activation.)

RIG-I-like helicases

Wow, so many acronyms! RIG-I here stands for retinoic acid-inducible gene I. RIG-I-like helicases (RLH- yup, yet another acronym!) float around in the cytoplasm, where they bind viral RNA via their helicase domains. Just like TLR7 (which also detects viral RNA), activation of RIG-I results in induction of type I IFN production.