T cells are white blood cells that help the body’s immune system to fight infections through destroying threats like viruses and infected cells. There is growing evidence that, in ME/CFS, T cell exhaustion (often referred to as immune exhaustion) is occurring – a state where T cells are chronically stimulated and become so overworked that they eventually stop functioning properly. A Penn Medicine news article describes – “In T cell exhaustion, the immune system switches from destroying everything to eliminate the pathogen to learning how to manage it. T cells sit in this under-responsive state. They’re not inert. They’re partially responsive. It’s as though the body’s [defence] goal has changed to keep the virus in check without causing too much damage along the way.” T cell exhaustion is known to occur in other diseases where there is chronic infection, such as HIV, Hepatitis, and malaria.
Using single-cell genomics – a powerful tool to analyse genetic information – researchers at Cornell University, conducted a detailed investigation exploring T cells at a genetic level in ME/CFS. The study involved 28 individuals with ME/CFS, fulfilling the IOM and Canadian Consensus Criteria – and 30 sedentary controls – who underwent an exercise challenge to provoke symptoms.
Findings
- T cells are exhausted
- In ME/CFS, T cells may be stuck in an activated state for too long and eventually become exhausted. The signs of T cell exhaustion included altered gene activity and metabolism and a disrupted ability to respond to threats.
- The researchers noted that following symptom provocation, there were elevated populations of various types of exhausted T cells (predominantly CD8+ T cells) and increased expression (production) of proteins such TOX an PD-1 which also indicate T cell exhaustion.
- The researchers mention that similarly T cell exhaustion may occur in long COVID, as indicated by certain patterns in the immune system (immunological signatures).
- Changes within T cells
- T cells in ME/CFS have changes in their genetic activity, and cells are essentially “rewired toward an exhaustion program”.
- They found genetic changes in a number of important pathways, such as those involving cell signalling, cell proliferation and cell death, which indicated that T cells were less active than normal (hypofunctional state).
- Role of inflammation
- Gamma delta (γδ) cells, a small subset of T cells, contribute towards inflammation through producing proteins known as cytokines and chemokines. Excessive inflammation enhances the sensitivity of T cells, leading them to be overworked and eventually exhausted.
- It was noted that in ME/CFS, gamma delta cells were substantially dysregulated.
Discussion
To study T cells in relation to ME/CFS, the researchers analysed genetic information following symptom provocation. Analysis revealed signs of exhaustion, including altered gene regulation and higher levels of exhaustion markers. The researchers suggested that ME/CFS leaves “epigenetic scars” on T cells, making T cells more likely to enter a state of exhaustion. Nevertheless, the researchers state that although they gathered strong evidence for T cell exhaustion in ME/CFS, “it remains unknown whether this state is a driver of pathology, or a consequence of prior triggering events”. Ultimately this research is a starting point and has generated further questions. The researchers suggest that future research should “continue to search for the specific viruses(es) involved in the disease, which will facilitate the analysis of virus-specific CD8+ T cells and improve the [characterisation] of exhausted T cells”. They further state that their observations “open numerous avenues for developing potential treatment options targeting T cell exhaustion and associated metabolic alterations, offering promising prospects for future research and, ultimately, therapeutic interventions in ME”.
Limitations of the study include a small sample size and the fact that the researchers predominantly focused on studying women with ME/CFS.
Read more about immune exhaustion in ME/CFS and long COVID
Read series on the immune system created by trustee, Dr Eleanor Roberts – Introduction | Part 1 | Part 2
