Transcriptional reprogramming primes CD8+ T cells toward exhaustion in Myalgic encephalomyelitis/chronic fatigue syndrome, 2024, Iu, Hanson et al

Is it? They're just looking at the phenotype of T-cells in circulation and as I linked above, (a) T-cells in circulation aren't the ones that are really doing anything (b) that phenotype can be the result of lower turnover due to differences in activity levels and exposure to new pathogens and (c) I cited a study that showed that even "exhausted" T-cells were still able to proliferate, execute antimicrobial functions and form quiescent memory cells upon further stimulation.

 

There may well be but it is hard to know what on earth that would mean. Cytokines released in association with cancer may shift traffic in all sorts of ways so you may be measuring a quite different subset of cells. And of course almost any abnormality will correlate with reduced survival in cancer patients. There is an industry (likely thousands of papers) based on trying to show that T cells are relevant to cancer. Recent work has shown that you can kill cancer with targeted T cells, yes, but much of the other stuff I would be wary of. But then my brother is a breast cancer biologist and writes articles on that!

 

The current state and future of T-cell exhaustion research
https://pmc.ncbi.nlm.nih.gov/articles/PMC10352049/

There have been different definitions of exhaustion based on varying combinations of metabolic, epigenetic, transcriptomic, and activation based phenotypic markers in this research field. For this reason you might see papers that don’t quite align with others. Doesn’t mean this is just a nebulous idea.

The research community is slowly working towards a consensus, and that being said all of the definitions so far have been based on combinations of measurable phenotypes. A useful excerpt

 

"exhaustion at the molecular level remains poorly defined and inconsistent across the literature."

Seems to sum it up.

 

Again, it doesn’t mean it’s just some nebulous idea, each varying definition is clearly based on a signature of measurable phenotypic markers

 

Does it matter though? Most of this research is sampling cells from circulation which isn't relevant to what is going on in specific tissues and is also confounded by other factors that affect T-cell lifespan/turnover in circulation.

On top of all of that, there aren't any reasonable hypotheses as to how T-cell exhaustion leads to ME/CFS pathology.

 

ME Research UK

Researchers suggest that ME/CFS leaves genetic changes on immune cells, known as T cells, making them more prone to T cell exhaustion - a state where they are overworked and eventually stop functioning properly.

Read more - https://bit.ly/tcellexhaustionmecfs

 

This video at 6hrs:27min to 6hrs:33min is interesting. Dr Hanson describes the teams work on CD8 T-cells that have been exposed to an antigen not only show markers of "exhaustion" differences they also show changes in energy production - metabolically from an energy measurement, ROS, AND gene expression.

https://www.youtube.com/watch?v=2M2b63pEZ2g

Chris Armstong and colleagues identified energy differences in naive B cells that lead to changed differentiation upon maturation. Could that be similar to what is happening in T cells in the paper of this thread. It could be the energy pathway changes that are driving the expression of "exhaustion" markers.

 

Shout out to @forestglip who posted a Cornell Chronicle news article in the NIH news thread that describes this work in laymans terms.
https://news.cornell.edu/stories/20...e-exhausted-chronic-fatigue-syndrome-patients

This quote near the end of the article describes what they hope to do next

 

There was a zoom today hosted by Solve ME with presenters Dr Lisa Selin from UMass and Dr Kumar from Hifibio.

Dr Selin stated that she was the first to identify T-cell exhaustion in ME/CFS and it was not by gene markers only. Using fresh cells they sorted Tcells by type with magnetic sorting and then measured their function both quiescent and activated vs healthy control. It was this measurement of function that led them to the conclusion that these cells were "exhausted" in their function. The study of this thread builds on that initial work.

When LSHTM did their large immune cell study it was with frozen blood - a few years ago I brought that to the attention of the Selin lab and they said that fresh blood + sorting of Tcells was needed to see the CD4+CD8+ subset.

During the webinar I asked via the Q&A if the Selin lab still needed fresh blood and Rivka the patient representative said they can use frozen. She stated that Dr Selin or Dr Gil should be contacted for the exact details.

All this is over my head. But they did share Dr Selin's email for those that have questions about the work - Selinlab@umassmed.edu . @Jonathan Edwards - you seem to be on the other side of the exhaustion story thinking it is not relevant - perhaps it's time for a "chat" with Dr Selin to see if you can be persuaded?

 

Just now seeing this thread. I remember skimming the paper when it came out. I believe similar findings are coming up in LC.

But overall, I don’t put much stock in T cell exhaustion as it relates to the etiology of ME/CFS. In the context of cancer survival it makes sense since active immune surveillance is the main thing stopping cancer from spreading. But if it is a relevant phenomenon in ME/CFS, I think it is far more likely to be a downstream consequence, rather than cause, of the disease.

I struggle to see how T cells that aren’t as active as they should be would explain any part of the illness.

The two options would be: 1) there’s some groundbreaking undiscovered function of T cells that is vital for keeping the whole system active and energetic all day long or 2) there’s some aberrant signaling somewhere else and this is one of the many down-the-river echoes of it.

I highly doubt it’s #1. In the case of #2, it’s a useful finding insofar as it’s one more peripheral piece of the puzzle.

 

There are two things I can think off as an armchair enthusiast.

1. The Selin lab has reported increased CD4+CD8+ T-cells in females (fresh blood, T cells sorted into CD8 cells first with magnetic sorting). Could these be Tcells that have failed to mature properly, similar to the Armstrong finding in maturation of B cells? [from the webinar : apparently there are a lot of CD4+CD8+ cells in the Thymus before they mature]

2. If the cytotoxic CD8 cells are less cytotoxic, which I thought was what Dr Selin is reporting, what is the consequence? Are there more "bad" cells in circulation? @DMissa reported higher PBMC cell death rate in ME/CFS vs Controls after a blood draw.

The Selin lab webinar described that in cancer the Tcell exhaustion is local to the cancer. In ME/CFS they are seeing it in circulating cells which shouldn't be the case. Exhaustion should be local as circulating cells are not doing much.

 

I agree that it's a weird and interesting finding. However, it still doesn't give any role for exhausted T cells in causing the disease, rather than being a consequence of it.

The entire point of an "exhausted" T cell (in its vague definition) is that it does less. It doesn't matter where the doing-less T cells are unless something about the body's functioning requires constant T cell activation for purposes beyond standard immune function. Which we don't have any evidence of.