Immune system underactive? T cell burnout may be why

Have you ever wondered why some people don’t seem to get sick?

My husband is a good example. While I seem to catch every bug that’s going around, he shrugs them off almost every time.

The key likely lies in the immune system. This complex network of cells and organs protects the body from infection by recognizing and destroying “intruders” like the bacteria, viruses and fungi that cause disease. The immune system is also a central player in fighting off cancer.

We know the immune system can malfunction in some people and become weak and underactive. Researchers have been exploring this phenomenon to get to the root cause, and in the process they’ve discovered something interesting at the molecular level….

How T cells get exhausted

One issue with an insufficient immune system is that the T cells gradually lose their ability to fight off invaders — a condition known as T cell exhaustion. A team of researchers in Germany has clarified the molecular mechanisms controlling this.

The exhaustion process can be traced to the mitochondria. These “powerhouses” are responsible for converting fuel into energy for all the cells in your body in a process called respiration. When mitochondrial respiration fails, it triggers a cascade of reactions that ends in the reprogramming of T cells and their eventual burnout.

To demonstrate that mitochondrial dysfunction is the actual cause of T cell exhaustion, the researchers developed a new genetic model that paralyzes mitochondrial respiration in T cells by switching off the mitochondrial phosphate transporter (SLC25A3).

Turning off SLC25A3 forces the T cells to switch to alternative metabolic pathways to meet their energy demands. This metabolic adaptation increases production of reactive oxygen species in the T cells. These elevated levels of oxygen radicals prevent the degradation of a particular protein (HIF-1-alpha) that, when it accumulates in the T cells, causes them to be reprogrammed and speeds up their exhaustion.

“This HIF-1-alpha-dependent control of T-cell exhaustion was previously unknown,” says Dr. Martin Vaeth at the Institute for Systems Immunology at Julius-Maximilians-Universität (JMU) Würzburg. “It represents a critical regulatory circuit between mitochondrial respiration and T cell function, serving as a ‘metabolic checkpoint’ in the process of T-cell exhaustion.”

What this means is this process may be counteracted through pharmaceutical or genetic enhancement of cellular metabolism, increasing the T cells’ longevity and functionality.

Improved immunotherapies

Vaeth says the researchers are optimistic that their findings will contribute to improved cancer immunotherapy. For example, CAR-T cell therapy has shown great effectiveness in treating leukemia and lymphoma. CAR-T cells are lymphocytes engineered in the lab to fight the respective form of cancer.

However, when it comes to solid tumors, CAR-T cells tend to get exhausted, limiting their success in fighting these forms of cancer.

“Our experiments demonstrate that augmented mitochondrial metabolism also increases the longevity and functionality of virus-specific T cells in chronic infections,” Vaeth says. Therefore, it’s plausible this strategy could be harnessed to enhance T cell-based immunotherapies for cancer.

The next step for the researchers is to explore how mitochondrial respiration influences the epigenetic programming of T cells as well as the way T cell metabolism interacts with the local tissue microenvironment. The latter is particularly important because the nutrient supply and oxygen tension in tumors differ considerably from healthy tissue. T cells must be able to actively respond to this challenging environment when fighting cancer.

The care and feeding of your mitochondria

As interesting as these results are, it will be years before they result in any therapeutics. Until then, there may be a couple of ways to help your own T cells avoid burnout by energizing your mitochondria…

One way is exercise. How does exercise help? It clears out the defective mitochondria through a process called mitophagy. And it gives your other mitochondria the kickstart they need to be more effective.

Consider this 3-minute HIIT workout. This high-intensity workout will not only juice up your mitochondria, it will also help improve your insulin mechanism and stave off insulin resistance.

Another way is to supplement pyrroloquinoline quinone (PQQ), a powerful antioxidant that is believed to not only improve the function of mitochondria but may help replenish them.

Sources:

1. Immunology: disfunction of mitochondria drives the exhaustion of T cells — EurekAlert!

2. Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming — Nature Communications