The subfornical organ is a nucleus for gut-derived T cells that regulate behaviour 2025 Wang et al

[Andy]

Abstract

Specialized immune cells that reside in tissues orchestrate diverse biological functions by communicating with parenchymal cells1. The contribution of the innate immune compartment in the meninges and the central nervous system (CNS) is well-characterized; however, whether cells of the adaptive immune system reside in the brain and are involved in maintaining homeostasis is unclear2,3,4.

Here we show that the subfornical organ (SFO) of the brain is a nucleus for parenchymal αβ T cells in the steady-state brain in both mice and humans. Using unbiased transcriptomics, we show that these extravascular T cells in the brain are distinct from meningeal T cells: they secrete IFNγ robustly and express tissue-residence proteins such as CXCR6, which are required for their retention in the brain and for normal adaptive behaviour. These T cells are primed in the periphery by the microbiome, and traffic from the white adipose and gastrointestinal tissues to the brain. Once established, their numbers can be modulated by alterations to either the gut microbiota or the composition of adipose tissue.

In summary, we find that CD4 T cells reside in the brain at steady state and are anatomically concentrated in the SFO in mice and humans; that they are transcriptionally and functionally distinct from meningeal T cells; and that they secrete IFNγ to maintain CNS homeostasis through homeostatic fat–brain and gut–brain axes.

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Open access link (may be time limited)

 

[Jonathan Edwards]

Perhaps it's the answer.
T cells in the brain.

 

[Utsikt]

Perhaps it's the answer.
T cells in the brain.

Do we have drugs that directly or indirectly affect T cells in the brain?

 

[Jonathan Edwards]

Do we have drugs that directly or indirectly affect T cells in the brain?

No idea.

 

[Murph]

There's a reference to photo-staining t-cells from fat and then finding them in the brain. I think. Is this paper saying t-cells are travelling from the fat to the brain?

 

[SNT Gatchaman]

Haven't read the paper but here's the Wikipedia page on the subfornical organ. One of the interface regions (like the area postrema) without the normal blood-brain barrier.

Of particular relevance would be these Wiki passages —

The subfornical organ is active in many bodily processes, including osmoregulation, cardiovascular regulation, and energy homeostasis. Most of these processes involve fluid balance through the control of the release of certain hormones, particularly angiotensin or vasopressin.

Additional research has demonstrated that the subfornical organ may be an important intermediary through which leptin acts to maintain blood pressure within normal physiological limits via descending autonomic pathways associated with cardiovascular control.

 

[Jonathan Edwards]

Additional research has demonstrated that the subfornical organ may be an important intermediary through which leptin acts to maintain blood pressure within normal physiological limits via descending autonomic pathways associated with cardiovascular control.



It must be the answer!

 

[Turtle]

Can such a tiny bit in the brain mess up so much?

 

[Creekside]

Can such a tiny bit in the brain mess up so much?

I'm more surprised that tiny bits of our brains don't mess us up more frequently. Just one transistor or angstroms thin trace in a computer failing can cause it to crash. We evolved various repair and bypass mechanisms because individuals without them didn't survive as well.

We probably have quite a few very specialized cells in specific regions of our brains that are somewhat like other cells, but the differences may make a difference in response to various chemicals. Maybe a slight increase in IFN-g in brain fluid has a minor effect on microglia and astrocytes, but has a larger effect on tanycytes, which are much fewer and much less studied. There might even be a sub-population of tanycytes--maybe only a dozen in the whole brain--that has an even more dramatic effect, resulting in ME.

 

[Jonathan Edwards]

I'm more surprised that tiny bits of our brains don't mess us up more frequently.

I agree. It intrigues me that the level of brain function that we think we vaguely understand is mostly carried out very nicely by bee brains the size of a pin head - including playing football. Most of the brain seems to be a vast, largely empty, dusty library set up just in case one day you might want to read a Punch edition from 1947. Pinhead sized structures could easily control a basic function.

 

[Creekside]

I'm not sure how fast the connection between gut and these brain-resident t-cells is. If you gain or lose a specific strain in your colon, how long does it take for the brain's response to signals from the body to change? I've had some ME-related food intolerances come and go quite abruptly, so maybe this is the mechanism?

I noticed that the study found sex-related differences in these t-cells, so that might fit ME.

This is the sort of research I think is important for diseases such as ME. If we didn't know about these special t-cells in the brain, we couldn't check them for abnormalities in PWME, and couldn't propose theories based on them.

 

[Jonathan Edwards]

I'm not sure how fast the connection between gut and these brain-resident t-cells is. If you gain or lose a specific strain in your colon, how long does it take for the brain's response to signals from the body to change? I've had some ME-related food intolerances come and go quite abruptly, so maybe this is the mechanism?

Do we know they are 'resident' or does that just mean they reside there when they are circulating around doing their police work? If colonic bacteria are showering off peptides or small metabolites I would have thought T cells would know about it within minutes but take a few hours to kick up a response maybe. Levels of bacterial garbage from gut may go up and down quite a bit with eating things. If a curry sends a load of stuff down to the colon in a bit of a hurry that may be the time when stuff gets picked up.

I am not a great fan of microbiome theories but having T cells sitting in your brain ready to signal seems an important thing to keep in mind, as you say.

 

[Creekside]

I am not a great fan of microbiome theories

I'm not supporting microbiome changes as a core part of ME's mechanism. However, I've experienced multiple ME-symptom-severity responses to foods or to what seemed to be dramatic changes in my microbiome, so I am interested in theories that connect the two. I think that if my gut was magically made perfect, I'd still have baseline ME symptoms, but I wouldn't have flareups from foods. I didn't notice much difference between PEM and food intolerances, so I expect they share some mechansism.

 

[SNT Gatchaman]

Nature News: How the brain spies on the gut: with help from newfound immune cells