A “Scarred Landscape” … Epigenetic T-Cell Study Moves the ME/CFS Field Forward

by Cort Johnson | Jan 15, 2025 | Autonomic Nervous System, Drugs, Epigenetics, Genetics, Homepage, Immune, Monocytes, Research, T-cells | 90 comments

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The “Transcriptional reprogramming primes CD8+ T cells toward exhaustion in Myalgiic encephalomyelitis/chronic fatigue syndrome” study just changed the immune “landscape” of ME/CFS. It grew out of Andrew Grissom and Maureen Hanson’s first single-cell RNA sequencing study, which was published last year.

With single-cell RNA sequencing, we move into a different world. (When you hear RNA sequencing, think gene expression).

This gene expression study used a new, more effective technique – single-cell sequencing.

Virtually all ME/CFS gene expression studies have used bulk sequencing, which assesses the gene expression of all the cells in a sample. Single-cell sequencing, on the other hand, measures the expression of all the genes of each cell in a sample.

Because everything is jumbled together, it’s impossible to determine which cells have gone wrong in bulk sequencing. While single-cell RNA sequencing is more expensive and requires more sophisticated equipment and data analytic techniques, it’s the only way for researchers to determine exactly which immune cells have gone bad—and that’s what happened here.

To give the NIH credit where credit is due, this study was funded by the NIH. Studies like this make it imperative that we move forward there.

The main finding of Grissom’s first single-cell study (“Single-cell transcriptomics of the immune system in ME/CFS at baseline and following symptom provocation“) was the pivotal role that classical monocytes played in the immune dysregulation found in ME/CFS. The study also found an intriguing monocyte-T-cell connection, however. In the ME/CFS patients, the classical monocytes were pounding the T-cells with signals – telling them to activate.

THE GIST

A recent study from the Hanson lab just changed the “landscape” of ME/CFS by uncovering some immune “scars” we didn’t know existed.
The study used a new technique called “single-cell RNA sequencing” which is able to uncover the gene expression of single cell types. It’s far more accurate and refined than anything that has been done in this disease before.
The study focused on T-cell exhaustion. When T-cells are activated, they, like other immune cells, change metabolically in order to produce more energy. If they are asked to do too much for too long, though, they’ll signal the retreat and ramp up their inhibitory networks that prevent them from becoming activated.
The study uncovered a wide array of markers in T-cells (including epigenetic factors, proteins, transfer factors, “poising”) suggesting that the activated T memory cells in ME/CFS were indeed exhausted.
The epigenetic finding was particularly interesting, as it suggested that an infection may, at one point, have rewired how ME/CFS patients’ genes were being expressed.
Rather poignantly, the authors wrote, “Taken together, these results suggest that ME leaves epigenetic scars on T-cells, which leaves them “primed for progression into late exhaustion states.”
They also proposed that exercise contributes to T-cell exhaustion and potentially contributes to inflammation, as well.
While memory T-cells got the lion’s share of attention, the authors reported that “notable” alterations in other T-cells were also found.
Writing that “the induction of T cell exhaustion is a multi-faceted process with various triggers,” the authors made it clear there were no easy answers to explain where the exhaustion is coming from.
The suspects were familiar; however, chronic infection, inflammation, or a chronically activated stress response (sympathetic nervous system activation) could all be driving the T-cell exhaustion.
Concerning the stress response, authors stated that a connection “between the autonomic nervous system and T-cell exhaustion “could have important implications for understanding how mental or physical exertion may drive PEM” and pointed to the dysregulated catecholamines (ANS neurotransmitters) Nath found in his recent intramural study.
Drugs that tackle T-cell exhaustion are available, and the authors wrote that “validating T-cell exhaustion in ME/CFS could open the door to the use of drugs that can return them to proper functioning”.
The authors also asserted that understanding T-cell exhaustion in other infection-associated illnesses, such as long COVID, will be critical to understanding these diseases.

This study suggest that both parts of the immune response – innate and adaptive – may be working in tandem to create problems in ME/CFS.

That’s a very interesting finding, given the hypothesis that the innate immune system (monocytes) is trying to compensate for an exhausted adaptive immune system (T- and-B- cells). It would make sense, after all, for an overwhelmed innate immune system to keep telling T-cells to “c’mon, wake up – I can’t handle this alone”. On the other hand, it may simply be that hyperactive monocytes started off the show – and by continually activating the T-cells – caused them to become exhausted.

Thus far, several studies have found evidence that CD8 T-cells are indeed exhausted (higher fatty acid oxidation rates, lower glycolytic rates, decreased mitochondrial membrane potential, reduced TNFα, and IFNγ production, increased expression of PD-1, and increased plasma levels of TIM-3).

When T-cells are activated, they, like other immune cells, they change metabolically in order to produce more energy. If asked to do too much for too long, though, they’ll signal the retreat and ramp up their inhibitory networks that prevent them from becoming activated. They may also shut down their engines if, in order to save the village, so to speak, they are about to destroy it, i.e., if they become too destructive.

The goal of this study was to use single-cell RNA sequencing to determine which subsets of T-cells had become dysregulated and exhausted, whether or not epigenetics was involved, and to assess protein levels.

Results

The study found no evidence of dysregulation in the naïve T-cells, which had not been activated, but it was a different story in the activated cells.

How ME/CFS-ey this finding was! Things were pretty much OK at baseline, but once the T-cells became stressed by being activated, problems showed up in spades.

Take the transfer factors. Transfer factors are small polypeptides or nucleotides that transfer information from one T-cell to another T-cell or to a B-cell. Instead of urging the T-cells on, the transfer factors in the ME/CFS patients told the activated T-cells to shut down.

Epigenetic changes – possibly triggered by an infection – put the T-cells from the ME/CFS patients on a road to exhaustion.

An epigenetic analysis found the same thing – epigenomic factors that controlled gene expression were “rewired” to produce T-cell exhaustion. The epigenetic finding was particularly interesting, as it suggested that an infection may, at one point, have rewired how ME/CFS patients’ genes were being expressed.

A lot of exhaustion seemed to be going on. A loss of “regulatory poising” in activated T-cells suggested T-cell exhaustion was present. Regulatory poising refers to what the immune system is “poised”, or ready, to accomplish. The fact that ME/CFS patients’ activated T-cells had lost poising about genes involved in cytokines, proliferation, and cytotoxicity indicated that they weren’t in any way ready to pounce on any pathogens, leaving them in a hypofunctional, or exhausted, state.

The elevated expression of several proteins (SLAMF6, TOX) also signaled that the ME/CFS patients’ T-cells were exhausted.

The authors wrote, “Taken together, these results suggest that ME leaves epigenetic scars on T-cells, which leaves them “primed for progression into late exhaustion states”. Then they proposed that exercise contributes to T-cell exhaustion, and potentially contributes to inflammation, as well.

While exhausted memory T-cells don’t produce as many pro-inflammatory cytokines as normal T-cells, they can produce them constantly. Plus, they secrete chemokines that recruit inflammatory monocytes.

While memory T-cells got the lion’s share of attention, the authors reported that “notable” alterations in other T-cells were also found. Perhaps tellingly, the γδ T cells that bridge the gap between innate and adaptive immunity exhibited “substantial dysregulation”.

Plus, CD8+ TN_NN cells, which play a key role in defeating intracellular viruses and ridding the body of cancer cells, were overly activated as well – suggesting that something was chronically stimulating these cells as well. Nancy Klimas’s statement, “If any diseases show chronic immune activation, ME/CFS and long COVID do” rang true in this study.

Cause?

A model of T-cell exhaustion from the paper.

Then came the big question: where is this T-cell exhaustion coming from, and what does it mean for ME/CFS? Unfortunately, there are no easy answers. The authors wrote that “the induction of T cell exhaustion is a multi-faceted process with various triggers”.

Because infections are a prime source of epigenetic shifts, the epigenetic “scars” found in the ME/CFS patients’ memory T-cells could, however, very well be the result of the infection that triggered the disease.

The authors also were unclear about whether the T-cell exhaustion found is “driving (the) pathology” in ME/CFS or is a consequence of some deeper problem. They noted that a chronic infection, inflammation, or a chronically activated stress response could drive T-cell exhaustion.

In fact, for all the attention given to infections, a chronic infection may have nothing to do with the T-cell activation and exhaustion seen in ME/CFS. The authors stated that a connection “between the autonomic nervous system and T-cell exhaustion “could have important implications for understanding how mental or physical exertion may drive PEM”. They pointed to the dysregulated catecholamines (ANS neurotransmitters) that Nath found in his recent intramural study.

The T-cells are involved, but it’s unclear who’s in the driver’s seat in ME/CFS: the T-cells, monocytes, B-cells, autonomic nervous system, mitochondria?

An Autonomic Nervous System Connection?

The authors didn’t dwell on the ANS aspect, but it’s worthwhile looking at it further. Sympathetic nervous system activation—which appears to be present in ME/CFS—can promote a microenvironment that favors T-cell exhaustion by suppressing the effector T-cells this study found dysfunctional.

Chronic activation of the stress response can also impair mitochondrial functioning, increase oxidative stress and inflammation, and produce harmful epigenetic changes—all of which can contribute to T-cell exhaustion. A recent Nature Highlight article, “Stress can be exhausting for T cells,” notes that immune checkpoint inhibitors are not always helpful in reviving T-cells, and point to the autonomic nervous system for answers.

With their ability to narrow blood vessels and tamp down blood flows, autonomic nervous system receptors called B2 ARs have generated great interest in ME/CFS. Dysfunctional B2 ARs can also promote T-cell exhaustion in a variety of ways. Narrowed blood vessels, which result in hypoxia and metabolic stress, can drive T-cells to exhaustion. Wirth and Scheibenbogen have outlined the role B2 ARs could be playing in calcium signaling and the mitochondrial problems in ME/CFS.

Treatment

In the end, it’s all about treatment. While this study does not by itself appear to open the door to a drug trial, this is how, molecular upon molecular finding, we get there.

Last year at the IMEC conference, Dr. Hanson stated that it takes a lot to convince immunologists that T-cell exhaustion is present. I don’t know if we’re there or not, but the data is accumulating, and data is what you need to get to try drugs that target T-cell exhaustion. The authors wrote:

“Validating T-cell exhaustion in ME/CFS could open the door to the use of drugs that can return them to proper functioning.”

Since the NIH has been funding much of the T-cell work, one would hope the data would lead to an NIH-funded trial.

If a jacked-up autonomic nervous system is the culprit—and we don’t know that it is—ChatGPT stated that “modulating ANS activity may help restore T-cell function in conditions like HIV or hepatitis” and pointed to several approaches: non-selective beta-blockers like propranolol, checkpoint blockade therapy, immune checkpoint inhibitors (e.g., anti-PD-1), and stress management (meditation, mind/body practices).

Conclusion

Multiple lines of evidence are converging on the T-cells.

For the first time that I can remember, an epigenetic analysis indicated that the triggering infection could have rejiggered ME/CFS patients’ genes in such a way as to leave their immune cells exhausted.

“Our epigenomic profiling of ME CD8+ T cells revealed multiple lines of converging evidence indicative of T cell exhaustion in ME.”

Uncovering the T-cell problems, particularly on the epigenetic levels, was a real achievement, but what really stuck out for me were the many potential connections. There’s a potential monocyte-T-cell connection, a memory T-cell-B-cell connection (memory T-cells activate B-cells), and an autonomic nervous system-T-cell connection. Being able to make connections suggests researchers are on the right track.

A possible monocyte-T-cell connection exists. Monocytes (upper right) and T-cells (middle left) showed up big time in Grissom’s first paper.

Plus, one would think this study would open the door to studying the other immune cells (B, NK) that appear to be exhausted in ME/CFS as well.

The authors clearly hoped this study would provide a template for studies in other conditions, including long COVID.

“As a major study profiling the epigenetic landscape of purified ME T cell subsets, we provide a critical resource not only to understand immune dysfunction in ME but to inform comparative studies on other infection-associated chronic conditions (IACC), including LC.”

Indeed, nothing even remotely like this study has yet been done in long COVID.

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The last blog of the donation drive ends on a nice note: converging lines of evidence indicate that T-cell exhaustion – something hardly dreamed of 10 years ago – may not only play a significant role in ME/CFS but could result in drug trials.

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