Mucosal associated invariant T cells restrict reactive oxidative damage and preserve meningeal barrier integrity and cognitive function, 2022, Zhang +

[hotblack]

Mucosal associated invariant T cells restrict reactive oxidative damage and preserve meningeal barrier integrity and cognitive function

Zhang Y, Bailey JT, Xu E, Singh K, Lavaert M, Link VM, D'Souza S, Hafiz A, Cao J, Cao G, Sant'Angelo DB, Sun W, Belkaid Y, Bhandoola A, McGavern DB, Yang Q.

Abstract
Increasing evidence indicates close interaction between immune cells and the brain, revising the traditional view of the immune privilege of the brain. However, the specific mechanisms by which immune cells promote normal neural function are not entirely understood.

Mucosal associated invariant T cells (MAIT) are a unique type of innate-like T cells whose molecular and functional properties remain to be better characterized. Here we report that MAIT cells are present in the meninges and express high levels of antioxidant molecules. MAIT cell deficiency in mice results in the accumulation of reactive oxidative species (ROS) in the meninges, leading to reduced expression of junctional protein and meningeal barrier leakage.

The presence of MAIT cells restricts neuroinflammation in the brain and preserves learning and memory. Together, our work reveals a new functional role for MAIT cells in the meninges and suggests that meningeal immune cells can help maintain normal neural function by preserving meningeal barrier homeostasis and integrity.

Link (Nat Immunol. 2022 Dec)
https://doi.org/10.1038/s41590-022-01349-1

 

[hotblack]

Came across this while looking at MAIT cells, also discussed in this article

Zhang et al. describe how meningeal MAIT cells maintain meningeal barrier integrity via the secretion of antioxidants, which also limit neuroinflammation and preserve spatial learning.

Meningeal MAIT cells maintain meningeal and brain function - PMC

Zhang et al. describe how meningeal MAIT cells maintain meningeal barrier integrity via the secretion of antioxidants, which also limit neuroinflammation and preserve spatial learning.

pmc.ncbi.nlm.nih.gov

 

[Jonathan Edwards]

1. Are all scientists now named Zhang?
2. Maybe Jackie Cliff was on to something.
3. The protective (negative) effect shows how easily predictions may turn out to be the opposite.

 

[Andy]

1. Are all scientists now named Zhang?

"Today, it is one of the most common surnames in the world at over 100 million people worldwide."

In comparison,
"2,442,977 Americans shared the surname Smith at the time of the 2010 census,[8] and more than 500,000 people shared it in the United Kingdom as of 2006."

 

[Jonathan Edwards]

So more than 7% of Chinese are called Zhang it seems.

 

[Jesse]

So more than 7% of Chinese are called Zhang it seems.

22% for Kim in South-Korea. I guess it's a good thing South-Korea isn't as big as China.

 

[AliceLily]

This could very well be what contributed to my ME. I had a sudden changed homeostasis after an infection when 20 years old with MAIT mucosa. I was never the same again. Left with localized pain. I later went on to get ME via a cold.

 

[hotblack]

I had a bit more of a dig and there’s more from the same group. Still mice but it’s obviously something someone has an interest in… not sure if it adds anything of use to us but for reference

MAIT cell deficiency exacerbates neuroinflammation in P301S human tau transgenic mice - Journal of Neuroinflammation

Background The role of immune cells in neurodegeneration remains incompletely understood. Accumulation of misfolded tau proteins is a hallmark of neurodegenerative diseases. Our recent study revealed the presence of mucosal-associated invariant T (MAIT) cells in the meninges, where they express...

link.springer.com

Frontiers | Aging induces T cells with distinct transcriptomic profiles and functions in brain-associated tissues

BackgroundAging is known to induce the emergence of distinct lymphocyte populations with unique molecular and functional characteristics. However, the impact...

www.frontiersin.org

 

[Jonathan Edwards]

I have a nasty feeling it may all be artefact but it is still fun.

 

[jnmaciuch]

Just started going through the paper. First thought is that they seem to have messed with the y axis for some of the violin plots showing RNA expression in Fig 2. They said that the scRNA-seq data was normalized and scaled but the range on those y axes suggest that they didn’t use normalized values for the plot itself, meaning that their findings for some of those anti-oxidant genes are based off 3-10 detected transcripts per cell

But it seems like they did quite a lot of mechanistic validation so I’m hoping later parts of the paper will compensate for that.

[Edit: qPCR validation for the lowly expressed genes. I’m satisfied]

 

[jnmaciuch]

So this is the killer figure from this paper. This is an assay where they’re basically testing meningeal barrier permeability based on how much SR101 gets through it. The first row is a wild type mouse compared to an MR1 knockout, which is supposed to have no MAIT. Since knocking out a gene may have off-target effects in cells you’re not interested in, the way you confirm that it’s the lack of MAIT causing this issue is to see if things go back to normal in a rescue—here they just intravenously replaced the missing MAIT cells in the MR1 knockouts.

And doing the rescue seemed to restore meningeal barrier permeability perfectly to normal.



And here in Fig 7 theyre showing that the same knock-out rescue perfectly restores cognitive function in these mice (if the rescue worked, the MR1-/- results should look like the PBS results and the MR1+/+ results should look like the MAIT results). Again, nearly perfectly matching the control MR1+/+ wildtype control every time. My classmates would be jealous about how well this rescue worked.

What is somewhat less convincing is their story about MAIT-secreted ROS scavengers facilitating this whole phenomenon, since doing a rescue with a potent ROS scavenger (glutathione) only partially made things look normal.

 

[hotblack]

Thanks for your expert eye @jnmaciuch

So the sceptical view is they may have found something (that MAIT cells are there and likely doing something which is helpful), but it’s in mice and the wider narrative they’ve drawn may be a stretch?

 

[jnmaciuch]

Thanks for your expert eye @jnmaciuch

So the sceptical view is they may have found something (that MAIT cells are there and likely doing something which is helpful), but it’s in mice and the wider narrative they’ve drawn may be a stretch?

Yep. At least for the behavioral measures of cognitive function—that was the weakest overall. They did show in other parts of the paper that the glutathione/ROS scavenger seemed to rescue other biological measures more adequately. It seemed a bit hit and miss.