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