The body increases temperature to fight off infections and illness. This temporary increase in temperature, also known as a fever, speeds up immune cell functions including metabolism and proliferation. Interestingly, researchers recently found that in a specific immune cell subset a fever can also generate mitochondrial stress, DNA damage, and cell death. These specific immune cells help fight off invading pathogens and are referred to as T cells.
Mitochondria are organelles within the cells of the body that provide energy and regulate metabolism. Recently, a lot of attention has been focused on T cell metabolism and subsequently, the mitochondria. Dysregulated metabolism in many chronic diseases leads to inactive T cells that are unable to identify and target infected cells. As a result, scientists are working to understand more about metabolic activity and the consequences of chronic illness on the immune system.
A recent article in Science Immunology, by Dr. Jeffrey Rathmell and others, demonstrate the mechanisms behind the effects of increased temperature on immune cells and how chronic inflammation could lead to the development of cancer. Rathmell is the Cornelius Vanderbilt Professor of Immunobiology and the Director of the Vanderbilt Center for Immunobiology at Vanderbilt University. His work focuses on T cell metabolism in inflammation and anti-tumor immunity. More specifically, Rathmell investigates the intracellular pathways activated by external stimuli that influence immune cell activity as a response to inflammatory disease.
Rathmell and the team focused on the effect of fever on immune cells because it is understudied. Despite understanding why the body increases temperature in response to infection, the effect of temperature on our cells are still unclear. In many cases it is difficult to change temperature for animal models without causing off-target effects and stressing the animals out. To first understand temperature influence on T cells, the team cultured cells at 39°C (or 102°F) and discovered that heat increased T cell metabolism, proliferation and effector activity. Additionally, the same T cells had lower immune suppressive activity. This discovery was expected since during an infection, immune cells need to be more effector-like and less suppressive to rid the tissue of disease.
Rathmell and others also discovered that a subset of T cells, known as Th1 cells develop mitochondrial stress and DNA damage. Some of these Th1 cells also died, which perplexed the researchers since these cells are necessary to fight infections. Interestingly, a small portion of the Th1 T cells die, while the others become more resistant to mitochondrial stress. The stress resistant cells then proliferate and produce pro-inflammatory proteins to treat the infection. Further investigation concluded that heat impairs mitochondrial pathways necessary for the production of cellular energy. Consequently, this impairment led to either cell death or DNA repair. Cells that repaired DNA became more resistant to stress and amplified the immune response. This mechanism was conserved in patients with chronic disease, including Crohn’s disease and rheumatoid arthritis.
The discovery of increased temperature on immune cells is foundational and provides an understanding of the mechanism behind chronic illness. More importantly, it could shed light on how cancer cells develop since many cancers are linked to chronic inflammation that results in increased body temperature. This work is paradigm shifting and enhances our knowledge of T cell biology and has the potential to be applied to other fields with the hope of improving treatments for those with chronic inflammatory disease, like cancer.
Article, Science Immunology, Jeffrey Rathmell, Vanderbilt University