T-cell exhaustion and ME/CFS
What does it mean for an immune cell to become 'exhausted'? Read on to find out...
T-cells are lymphocytes, a type of white blood cell, and form a key part of the immune system. There are different types of T-cells, which have different functions, and sometimes they transform from one type to another.
Naive, killer, and memory T-cells
Three of the main types of T-cells are naive, killer and memory. Naive T-cells are always present in the body. When the immune system recognizes an invader and launches an immune response, naive T-cells are activated and transform into cytotoxic T-cells, also known as killer T-cells, which destroy cells that have been infected with a virus or cancer. Cytotoxic T-cells also undergo clonal expansion, making a vast number of copies of themselves.
Once the infection or cancer has been destroyed, 90-95% of the cytotoxic T-cells die and the rest transform into memory T-cells, which ensure that if the same infection or cancer ever returns, the immune response will be faster and stronger the second time around.
T-cell exhaustion
About 20 years ago a new type of T-cell was described, one which is only found in people with long-term infections or cancer. Compared to cytotoxic T-cells, cells of this new type are not as good at killing infected or cancerous cells, they don’t make as many copies of themselves, and they express proteins and send chemical signals that tend to dampen down the immune response overall. These became known as exhausted T-cells. The longer an infection drags on, the more ‘exhausted’ the T-cells become.
The T-cell response is central in the adaptive immune-mediated elimination of pathogen-infected and/or cancer cells. This activated T-cell response can inflict an overwhelming degree of damage to the targeted cells, which in most instances leads to the control and elimination of foreign invaders. However, in conditions of chronic infection, persistent exposure of T-cells to high levels of antigen results in a severe T-cell dysfunctional state called exhaustion. T-cell exhaustion leads to a suboptimal immune-mediated control of multiple viral infections including the human immunodeficiency virus (HIV).
T-cell exhaustion in HIV infection, Fenwick et al, 2019
Long-term immune responses can cause harm to the body, and T-cell exhaustion probably evolved to protect us from this harm. On the other hand, T-cell exhaustion suppresses the immune system and prevents it from fighting off infections or cancer. Researchers believe that, at least in some circumstances, T-cell exhaustion is bad for us, and in recent years they have looked for drugs to reverse it.
T-cell exhaustion and cancer
We normally think of the immune system as protecting us from viruses and bacteria, but it also protects us from some kinds of cancer. Cancer patients have a long-term immune response, and over time they can develop T-cell exhaustion.
There have been promising preclinical trials of immunotherapy drugs which reverse T-cell exhaustion in cancer patients. It is hoped that these drugs will re-invigorate the immune system, allowing it to fight off the cancer more effectively.
Ongoing immune responses in ME/CFS and Long Covid
Exhausted T-cells have been found in ME/CFS and Long Covid. This is significant because in both illnesses it is suspected that there is chronic or repeated viral infection driving a long-term immune response, and T-cell exhaustion adds to the evidence for this.
Beyond this, there is a theory that T-cell exhaustion may actually be the fundamental cause of ME.
Immune dysregulation and the T-cell exhaustion theory of ME/CFS
Researcher Liisa Selin believes that T-cell exhaustion may cause immune dysregulation.
A person is considered to have a dysregulated immune system if they have very different amounts - either more or less - of various cells and chemicals involved in the immune system, than are normally found. The immune system is very complex and has many different parts - cells, antibodies, and chemical messengers like cytokines - all balanced against each-other in an intricate dance. While we need our immune response to protect us from infection, parts of the immune response can be harmful - for example, too much inflammation can cause damage to cells. When the immune system is dysregulated, the harmful parts are not held in check and can run amock, causing damage.
Researchers aren’t sure what the consequences of immune dysregulation could be. Dr Selin theorises that immune dysregulation caused by T-cell exhaustion could be the fundamental cause of ME/CFS. If this is true, drugs with the ability to reverse T-cell exhaustion could prove to be promising treatments for ME/CFS, and perhaps Long Covid as well.
Further reading and viewing
T-cells at biologydictionary.net
T cell exhaustion, E John Wherry 2011
CD8 T Cell Exhaustion in Chronic Infection and Cancer: Opportunities for Interventions, Hashimoto et al 2018
T-cell exhaustion in HIV infection, Fenwick et al, 2019
Remodeling of T Cell Dynamics During Long COVID Is Dependent on Severity of SARS-CoV-2 Infection, Wiech et al, 2022
Altered T Cells, Video lecture by Dr. Liisa Selin, 45 min