TLRs in all cells or just professional APCs?
June 24, 2009 4:59 AM Subscribe
MolecularBiologyFilter: Embarrassingly easy question for any immunologists out there: are Toll-like receptors (or other pathogen recognition receptors) only expressed in professional antigen presenting cells (DCs, macrophages etc), or are they in e.g. epithelial cells too?
Some papers I've read imply that TLRs are only expressed in in antigen presenting cells like dentritic cells, macrophages etc. and maybe some effectors like NKs. But while the small mountain of papers I've skimmed -- or even my ageing immunology textbook -- give reams of really lovely detail about their sequences, structures and mechanisms, I can't find anything that explicitly tells me where the darn things are found.
I get the strong impression that it's one of those "too obvious to bother mentioning" things, but I don't have a tame immunologist nearby today. Can anyone help me out?
Background for curious non-biologists:
You've probably heard of "antibodies", molecules that your body produces in huge variety to recognise anything "non-self" like bacteria, viruses and in my case pollen, making every summer a living hell. Every person (indeed, every mammal) has different set of antibodies because we make them almost from scratch, in a process that biologists call random but a mathematician might call chaotic. By making them at random, it means that the immune system is generating antibodies against stuff it hasn't encountered yet; by sheer luck, a tiny proportion of them will probably be about right to recognise an infection you've never had before and nuke it before you even know you're ill. The immune system is awesome.
My question is about "Toll-like receptors." These are similar to antibodies in purpose, but we all express roughly the same ones. Unlike antibodies, TLRs' structures are fixed, encoded by our genes. Their job is to recognise really common hallmarks of infection, e.g. lipopolysaccharides found in all bacteria's outer membranes, or unmethylated CpG motifs, which are really typical of virus DNA but not our own. These TLRs are often the earliest things that get triggered at the start of an immune response (they're part of the "innate" response) and lead to ramping up the activity of the more powerful and adaptive response that involves the more clever stuff like antibodies and/or killer cells specifically customised to target the new infection (the slower but more powerful "adaptive" response).
I want to know if they're in all your cells (so a random lung cell that gets infected with, say, a coronavirus will trigger an internal response to help stop the infection before it starts and thus prevent your cold) or if they're only in the cells that roam your body deliberately swallowing everything they can, looking for new pathogens.
Oh, and the "Toll" in TLR apparently means "Wow!" in German, after what the woman who discovered them shouted when she first saw her experiment's results.
Some papers I've read imply that TLRs are only expressed in in antigen presenting cells like dentritic cells, macrophages etc. and maybe some effectors like NKs. But while the small mountain of papers I've skimmed -- or even my ageing immunology textbook -- give reams of really lovely detail about their sequences, structures and mechanisms, I can't find anything that explicitly tells me where the darn things are found.
I get the strong impression that it's one of those "too obvious to bother mentioning" things, but I don't have a tame immunologist nearby today. Can anyone help me out?
Background for curious non-biologists:
You've probably heard of "antibodies", molecules that your body produces in huge variety to recognise anything "non-self" like bacteria, viruses and in my case pollen, making every summer a living hell. Every person (indeed, every mammal) has different set of antibodies because we make them almost from scratch, in a process that biologists call random but a mathematician might call chaotic. By making them at random, it means that the immune system is generating antibodies against stuff it hasn't encountered yet; by sheer luck, a tiny proportion of them will probably be about right to recognise an infection you've never had before and nuke it before you even know you're ill. The immune system is awesome.
My question is about "Toll-like receptors." These are similar to antibodies in purpose, but we all express roughly the same ones. Unlike antibodies, TLRs' structures are fixed, encoded by our genes. Their job is to recognise really common hallmarks of infection, e.g. lipopolysaccharides found in all bacteria's outer membranes, or unmethylated CpG motifs, which are really typical of virus DNA but not our own. These TLRs are often the earliest things that get triggered at the start of an immune response (they're part of the "innate" response) and lead to ramping up the activity of the more powerful and adaptive response that involves the more clever stuff like antibodies and/or killer cells specifically customised to target the new infection (the slower but more powerful "adaptive" response).
I want to know if they're in all your cells (so a random lung cell that gets infected with, say, a coronavirus will trigger an internal response to help stop the infection before it starts and thus prevent your cold) or if they're only in the cells that roam your body deliberately swallowing everything they can, looking for new pathogens.
Oh, and the "Toll" in TLR apparently means "Wow!" in German, after what the woman who discovered them shouted when she first saw her experiment's results.
Best answer: Yup, they're expressed all over the place. Intestinal epithelial cells definitely express them, although not always in large amounts (plus they may not be activated by their ligands thanks tolerance mechanisms). I'm right this minute measuring cytokine outputs from some IECs to see if the TLR was activated in my assay or not.
A pub med search of TLR expression brings up 211 review articles listing a bunch of different diseases (cardiovascular, airway, intestinal) and mentioning a few different cell types. There should be a general review around discussing the different TLRs and where they work, in face I'm sure I've read one recently. Unfortunately I've been travelling and not keeping up with my reference library plus my notes are a mess so I can't track it down right now (probably in. These two might be a place to start though? If you have more specific questions about TLR expression in epithelial cells, particularly IECs, let me know.
posted by shelleycat at 5:42 AM on June 24, 2009
A pub med search of TLR expression brings up 211 review articles listing a bunch of different diseases (cardiovascular, airway, intestinal) and mentioning a few different cell types. There should be a general review around discussing the different TLRs and where they work, in face I'm sure I've read one recently. Unfortunately I've been travelling and not keeping up with my reference library plus my notes are a mess so I can't track it down right now (probably in. These two might be a place to start though? If you have more specific questions about TLR expression in epithelial cells, particularly IECs, let me know.
posted by shelleycat at 5:42 AM on June 24, 2009
Yup, they're expressed all over the place.
By the way, I don't mean to imply that every cell has them because I don't think that's true. But they're certainly present at various mucosal surfaces and more widespread than just professional APCs (IECs can present antigens too actually, they're very cool cells).
posted by shelleycat at 5:46 AM on June 24, 2009
By the way, I don't mean to imply that every cell has them because I don't think that's true. But they're certainly present at various mucosal surfaces and more widespread than just professional APCs (IECs can present antigens too actually, they're very cool cells).
posted by shelleycat at 5:46 AM on June 24, 2009
Response by poster: shellycat's second link lead me, via some newly-informed searching, to this very nice review of TLRs generally. That review was later cited by this article about TLR3 in bronchial epithelia, which is so perfect for what I'm writing that I'm half inclined to skip across town and buy its authors a drink.
Thanks very much, both of you! This is for a last-minute side note buried in the introduction to the PhD thesis that I'll be submitting later this week. A relatively minor thing, but you've made a stressed-out grad student's day that much better.
Where else on the web could I get equally fast and informed answers about Cantonese pop music and molecular biology? A steal at $5!
posted by metaBugs at 6:26 AM on June 24, 2009
Thanks very much, both of you! This is for a last-minute side note buried in the introduction to the PhD thesis that I'll be submitting later this week. A relatively minor thing, but you've made a stressed-out grad student's day that much better.
Where else on the web could I get equally fast and informed answers about Cantonese pop music and molecular biology? A steal at $5!
posted by metaBugs at 6:26 AM on June 24, 2009
Response by poster: Two minor updates:
(a) I meant "shelleycat", of course. Sorry about that.
(b) Dispiritingly, none of the authors on the earliest Toll papers linked by the reviews have German-sounding names, making me doubt the story about why they're called "Toll". I really liked that story. Oh well, at least we still have all the other daft Drosophila gene names.
posted by metaBugs at 6:35 AM on June 24, 2009
(a) I meant "shelleycat", of course. Sorry about that.
(b) Dispiritingly, none of the authors on the earliest Toll papers linked by the reviews have German-sounding names, making me doubt the story about why they're called "Toll". I really liked that story. Oh well, at least we still have all the other daft Drosophila gene names.
posted by metaBugs at 6:35 AM on June 24, 2009
The review you link isn't the one I had, is better, and will be helpful to me too. So cheers!
And being at work at 2 am after a full day and with two hours still to go and an early start again tomorrow I fully understand the stressed out PhD student thing. I'm glad I could help.
posted by shelleycat at 6:56 AM on June 24, 2009
And being at work at 2 am after a full day and with two hours still to go and an early start again tomorrow I fully understand the stressed out PhD student thing. I'm glad I could help.
posted by shelleycat at 6:56 AM on June 24, 2009
Best answer: About the naming of Toll: The supposed original phrase was "Das war ja toll" uttered by the now Nobel Laureate Christiane Nüsslein-Volhard. It has been discussed here on Metafilter previously focussing mainly on the choice of "weird" as the translation.
posted by Cold Lurkey at 7:13 AM on June 24, 2009
posted by Cold Lurkey at 7:13 AM on June 24, 2009
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