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

Transcriptional reprogramming primes CD8+ T cells toward exhaustion in Myalgic encephalomyelitis/chronic fatigue syndrome

Significance
Myalgic encephalomyelitis/chronic fatigue syndrome (ME) is a serious disabling chronic illness that lacks FDA-approved therapies.

Comprehensive transcriptomic, epigenomic, and flow cytometric profiles of primary CD8+ T cell subsets implicate T cell exhaustion in pathophysiology. We show that T cells in ME cases are epigenetically predisposed toward terminal exhaustion and that exhaustion markers are upregulated following exercise challenge. Using single-cell genomics, we provide important information about the role of CD8+ T cell exhaustion development and progression.

Our findings are consistent with the hypothesis that chronic viral infection is a factor in ME; by dissecting the molecular basis of T cell dysfunction in ME, we offer potential avenues for treatment.

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME) is a severe, debilitating disease, with substantial evidence pointing to immune dysregulation as a key contributor to pathophysiology.

To characterize the gene regulatory state underlying T cell dysregulation in ME, we performed multiomic analysis across T cell subsets by integrating single-cell RNA-seq, RNA-seq, and ATAC-seq and further analyzed CD8+ T cell subpopulations following symptom provocation. Specific subsets of CD8+ T cells, as well as certain innate T cells, displayed the most pronounced dysregulation in ME. We observed upregulation of key transcription factors associated with T cell exhaustion in CD8+ T cell effector memory subsets, as well as an altered chromatin landscape and metabolic reprogramming consistent with an exhausted immune cell state. To validate these observations, we analyzed expression of exhaustion markers using flow cytometry, detecting a higher frequency of exhaustion-associated factors.

Together, these data identify T cell exhaustion as a component of ME, a finding which may provide a basis for future therapies, such as checkpoint blockade, metabolic interventions, or drugs that target chronic viral infections.


https://www.pnas.org/doi/epub/10.1073/pnas.2415119121

 

Are any of these interventions things that already exist/are licensed?

 

Probably just me being dim, but I don't really understand the exhaustion idea. Are the T cells not doing what they're supposed to, or not doing enough of it? Descriptions of immune cells seem to present most of them as transient entities that are being replaced all the time anyway.

 

TN = naive T cells
TM = memory T cells

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Mastering an exhausting marathon: how CD8+ T cells fine-tune metabolic fitness (2022, Immunology and Cell Biology)

Defining ‘T cell exhaustion’ (2019, Nature Reviews Immunology)

Is There a Positive Side to T Cell Exhaustion? (2019, Frontiers in Immunology)

 

It's mostly based on what receptors they express. Those that express less of certain receptors (or more inhibitory receptors) are less likely to respond to activating signals.

But here is the key point that seems to be missed - those expression patterns are the result of their microenvironment and survival time.

People with ME/CFS in general have lower activity levels and lower activity intensity peaks. This leads to lower turnover of T-cells and can be the cause of the observed findings even in the absence of any pathogenicity. More "exhausted" T-cells doesn't actually imply any sort of practical immunodeficiency.

"Influence of Exercise on Exhausted and Senescent T Cells: A Systematic Review"
https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2021.668327/full

 

For what it's worth, this study compared to sedentary controls. Though I imagine even people who barely leave the house would probably be sitting up more than people with ME/CFS. And I can't find any specific details on activity levels.

I think any markers found that differ from controls that are less sedentary than ME/CFS should be replicated by testing with controls that are more sedentary, preferably fully bedbound people.

 

And they had a huge difference in reported scores on the Bell Activity Scale.

 

Thanks so much, that's really helpful!

 

Some more information on the lifespan of T-cells (and note that a majority of T-cells are tissue-resident, rather than in blood.)

"Memories that last: Dynamics of memory T cells throughout the body" (2023)
https://onlinelibrary.wiley.com/doi/full/10.1111/imr.13211

They also note another study that showed that despite T-cells being iteratvely stimulated until they expressed 'exhaustion' markers, they still were able to proliferate, execute antimicrobial functions and form quiescent memory cells upon further stimulation. (Stimulation was: "We activated mouse T cells in vivo using acute heterologous prime–boost–boost vaccinations" - for 50+ rounds)

 

I have no ability to judge the quality of this work on its scientific merit, but one major point in favor of such an explanation is that it is coherent with the problem as it relates to an infectious trigger and a resulting exertion intolerance, especially exercise, since t-cells are also involved in repairing the damage that exertion causes. That is, it checks most of the necessary conditions for an explanation of ME/CFS.

IIRC, exercise produces an inflammatory (or something like it) response short term, but reduces inflammation long term. That short-term response deals with repairing the damage and restoring the metabolic status quo. An increase that may be enough to tip a fragile system that requires very little to push it over the edge.

What is harder to explain though is when things get more severe, where simple things like even low-level noise can be excruciatingly painful.

But it does make overall sense in that no system can be infinitely activated. Especially biological systems require periods of rest to return to a functioning state. Hence: sleep. Lots of sleep. Literally 1/3 of our lives spent in a near paralytic state.

One overlap that can make sense is how active individual cells actually are from simply living. You can see videos of that, I saw an incredible one recently. Cells aren't cemented in place like bricks in a wall. They move, morph and shift a lot. They do a lot of work even when the body isn't moving at all.

A good example of where resource exhaustion makes sense is war. Anyone who knows anything about war knows that wars are first and foremost about logistics. You can have 1M troops to their 500k troops and if they have 4x as much resources they will likely beat you. When your soldiers run out of ammunition, it becomes a shooting gallery, even if your troops outnumber them 10:1.

Any coherent explanation of ME/CFS, IMO, has to make sense of that odd overlap between an immune response to pathogen and the cellular repair and overall maintenance mechanisms of the body, which is one of the most likely explanation for why exertion is so damaging, because it literally is and we have repair mechanisms for this. It has to be something that is involved in both.

And sure enough many of the immune system's cells aren't just foot soldiers, they are also the entire repair and maintenance apparatus, and they likely can't do both at the same time indefinitely. Eventually something has to give, and the system has to retreat to a lower state that disables global functioning while a slow-acting system tries to return to some equilibrium. An equilibrium that can be thrown back entirely from a single additional infection.

This is such a common problem with LC, people who had recovered fully or almost end up in an even worse state from a single infection, whereas the most common trigger leading to PEM collapse is exercise, pushing through the system breaking down.

At some point explanations have to plausibly explain reality, which almost no theoretical model bothers with, and which biopsychosocial models explicitly ignore, even counter. So at least this here is coherent in that regard.

 

Would t-cell exhaustion explain why many PWME rarely get viral infections? Could the dysfunction be just for muscle exertion signals?

I like Snow Leopard's explanation of us having lower turnover, thus resulting in a bunch of elderly t-cells hobbling around.

 

Press release:
https://www.eurekalert.org/news-releases/1066876

News Release 3-Dec-2024
Immune T cells become exhausted in chronic fatigue syndrome patients
Peer-Reviewed Publication

Cornell University



ITHACA, N.Y. – Chronic fatigue syndrome creates conditions where pathogen-killing immune T cells become exhausted, according to a new Cornell University study.

The study’s authors knew the immune system was dysregulated in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) but wondered which parts shift with the condition. A systematic exploration revealed that key CD8+ T cells displayed one of the most pronounced signatures of dysregulation, with signs of constant stimulation that lead to an exhausted state, a condition that is well-studied in cancer.

“This is an important finding for ME/CFS because now we can examine the T cells more carefully, and hopefully by looking in the exhausted cells we can start to get hints as to what they are responding to,” said Andrew Grimson, professor of molecular biology and co-corresponding author of the study. Maureen Hanson, professor of molecular biology and genetics, is the other corresponding author.

“Therapies have been developed to reverse T cell exhaustion as treatments for cancer,” Hanson said. “Our findings raise the question of whether such anti-exhaustion drugs might also be helpful in ME/CFS.”

Strong evidence for the phenomenon of T cell exhaustion in ME/CFS has also been reported in long COVID, Hanson added.

“Immune cells from ME/CFS patients exhibited higher levels of proteins on their surface that are characteristic of cells that have become exhausted, which can be caused by long-term exposure to a virus protein or by continuous stimulation of the immune system, a state that is also found in cancer patients,” Hanson said.

Future work will try to determine whether a virus is in fact involved, which is currently not known. “We need to understand what is pushing them to this exhausted state,” Grimson said.

The team also plans to take cells from patients and controls, purify those cells and treat patients with drugs that reverse exhaustion and see if the immune cells resume normal function. If CD8+ T cell exhaustion can be reversed, the next question is whether such reversal actually benefits a patient, as exhaustion can have protective qualities.

For additional information, read this Cornell Chronicle story.

Cornell University has dedicated television and audio studios available for media interviews.

-30-

Journal
Proceedings of the National Academy of Sciences

DOI
10.1073/pnas.2415119121

Article Title
Transcriptional reprogramming primes CD8+ T cells toward exhaustion in Myalgic encephalomyelitis/chronic fatigue syndrome

Article Publication Date
2-Dec-2024

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https://news.cornell.edu/stories/20...e-exhausted-chronic-fatigue-syndrome-patients

Immune T cells become exhausted in chronic fatigue syndrome patients
By Krishna Ramanujan, Cornell Chronicle
December 3, 2024

Debilitating chronic fatigue syndrome creates conditions where a kind of immune cell that identifies and kills pathogens, known as a T cell, becomes exhausted, according to a new study that points the way for important new lines of investigation.

The study’s authors knew the immune system was dysregulated in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), so they began by asking, which parts shift with the condition? A systematic exploration revealed that key CD8+ T cells displayed one of the most pronounced signatures of dysregulation, with signs of constant stimulation that lead to an exhausted state, a condition that is well-studied in cancer.

ME/CFS affects an estimated 3 million people in the United States and some 65 million worldwide, leaving some patients ill for decades and unable to work. Symptoms include overwhelming fatigue that is not helped by rest, and can also include brain fog, body pains, headaches, difficulty sleeping and prolonged increases in symptoms after mild physical exertion or exercise. Causes are unknown and there is no treatment for the disease.

“This is an important finding for ME/CFS because now we can examine the T cells more carefully, and hopefully by looking in the exhausted cells we can start to get hints as to what they are responding to,” said Andrew Grimson, professor of molecular biology and genetics in the College of Arts and Sciences.

Grimson is co-corresponding author of the study, published Dec. 2 in the Proceedings of the National Academy of Sciences. Maureen Hanson, Liberty Hyde Bailey Professor in the Department of Molecular Biology and Genetics (College of Agriculture and Life Sciences), is the other corresponding author.

“Therapies have been developed to reverse T cell exhaustion as treatments for cancer,” Hanson said. “Our findings raise the question of whether such anti-exhaustion drugs might also be helpful in ME/CFS.”

Strong evidence for the phenomenon of T cell exhaustion in ME/CFS has also been reported in long COVID, Hanson added.

The study was led by co-first authors David Iu, a doctoral student in Grimson’s lab, and Jessica Maya, Ph.D. ‘24, formerly in Hanson’s lab and currently a researcher at the Centers for Disease Control and Prevention.

In a paper published earlier this year, Grimson and collaborators used a technology called single cell RNA sequencing to examine and identify all the circulating immune cells in ME/CFS patients. In the current paper, they used that data to examine which of the different types of T cells, including CD8+ T cells, were most altered in ME/CFS patients.

“That pointed us in the direction of CD8+ cells,” Grimson said. After purifying those cells, they used additional advanced technologies to precisely determine which genes were being expressed and pinpoint which genes were getting switched on or off.

“When we looked at all of the differences [compared to normal functioning], they really pointed us towards an exhaustion-like state for the CD8+ T cells,” Grimson said.

Meanwhile, in Hanson’s lab, Maya led a different approach of purifying patients’ T cells and then determining expression patterns of proteins on the surface of these cells. The team examined two series of different markers on the various proteins, one of which allowed them to subdivide all the different types of CD8+ T cells, while the other allowed them to detect proteins known to be involved in exhaustion.

“Immune cells from ME/CFS patients exhibited higher levels of proteins on their surface that are characteristic of cells that have become exhausted, which can be caused by long-term exposure to a virus protein or by continuous stimulation of the immune system, a state that is also found in cancer patients,” Hanson said.

Future work will try to determine whether a virus is in fact involved, which is currently not known. “We need to understand what is pushing them to this exhausted state,” Grimson said.

The team also plans to take cells from patients and controls, purify those cells and treat patients with drugs that reverse exhaustion and see if the immune cells resume normal function. If CD8+ T cell exhaustion can be reversed, the next question is whether such reversal actually benefits a patient, as exhaustion can have protective qualities.

Another future line of inquiry will include distinguishing T cell receptors in exhausted cells from patients, to try to find which molecules those T cell receptors are recognizing, and if from those clues, they can work out whether specific pathogens are involved.

The collaborative research was enabled by the Cornell Center for Enervating Neuroimmune Disease, which was established in 2017 and has received an additional five-year, $9.5 million grant from the National Institutes of Health’s National Institute of Allergy and Infectious Disease to study ME/CFS.

Co-authors include Jennifer Grenier, director of the Genomics Facility in the Cornell Institute of Biotechnology.

The study was funded by the National Institute of Neurological Disorders and Stroke, the National Institute of Allergy and Infectious Diseases, the National Institute on Drug Abuse, the National Heart, Lung, and Blood Institute, the National Human Genome Research Institute, all part of the National Institutes of Health; and the Amar Foundation.

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You are not being dim. I think you have hit the nail on the head. I don't see the validity of the exhaustion idea as an immunologist.

Edit: andI are with SL that any skewing is very likely to be due to shift in traffic and lifespan.

The key problem with studies like this is that circulating immune cells are more or less by definition the ones doing nothing very interesting. The ones doing interesting things are outside the blood in tissues and lymph nodes.

 

Instead of the possibly misleading "exhaustion", older cells have different responses, and maybe even different roles. On a construction site, you get the young guys to scamper around doing certain jobs, learning from them, and have the experienced guys doing jobs that require that experience. The older guys aren't "exhausted", and might be able to outperform the young guys at some physically-demanding tasks just because of muscle training and doing the job smarter.

 

T cell exhaustion isn’t an idea it’s a measurable phenomenon.

 

Certain measurements are referred as T cell exhaustion but I very much doubt that has any reliable functional meaning in real people rather than mice.

If you think about it, what experiment could have been done to reliably show that there was a functional meaning in the context of various human diseases?

 

1) What are examples of anti-exhaustion drugs?
2) What protective qualities are they referring to?

 

The quote looks very confused to me. This idea - yes an idea- that T cells are exhausted and can be de-exhausted in a useful way seems to me to completely ignore crucial dynamic and compartmental factors. T cell populations are constantly dividing, undergoing maturation and dying off at different rates in different places. What they look like in a place like blood, where they are doing nothing much, seems unlikely to be a reliable index of anything much.

 

Pretty sure there are dozens of papers showing it to correlate with reduced survival in human cancer patients

 

It looks like it correlates to less exercise too, though, which might be what this ME/CFS study is looking at depending on how well they controlled for activity.

Influence of exercise on exhausted and senescent T cells: a systematic review, 2021, Rao et al