Research from Vanderbilt University Medical Center has revealed that fever temperatures enhance the metabolism, replication, and functionality of immune cells; however, they also induce mitochondrial stress, DNA damage, and cell death in a specific group of T cells.
Published on September 20 in the journal Science Immunology, these findings provide insights into how cells react to heat, which may shed light on the role of chronic inflammation in cancer development.
Jeff Rathmell, PhD, a Cornelius Vanderbilt Professor of Immunobiology and the study’s lead author, noted that the effects of fever temperatures on cells are not well-explored. Many studies have focused on how extreme temperatures affect agriculture rather than immune responses. He explained that it’s tricky to alter the temperature in animal models without stressing them, and laboratory cell cultures are typically maintained at standard human body temperature: 37 degrees Celsius (98.6 degrees Fahrenheit).
“Normal body temperature isn’t necessarily reflective of most inflammatory processes, yet few investigations have aimed to determine what occurs with temperature variations,” Rathmell, who is also the director of the Vanderbilt Center for Immunobiology, stated.
Graduate student Darren Heintzman became curious about the impact of fevers due to personal experiences: his father suffered from an autoimmune disease leading to prolonged fever. He stated, “It was intriguing to consider how an increased temperature set-point might affect the body.”
Heintzman grew immune system T cells at 39 degrees Celsius (approximately 102 degrees Fahrenheit) and discovered that this elevated heat boosted the metabolism, replication, and inflammatory activity of helper T cells while diminishing the suppressive function of regulatory T cells.
“This aligns with a typical immune response to infection: effector T cells should be more responsive to pathogens, while regulatory T cells should reduce their suppression,” Heintzman explained.
However, an unexpected finding emerged: a subset of helper T cells known as Th1 cells experienced mitochondrial stress, DNA damage, and some cell deaths. The researchers found this perplexing, as Th1 cells are crucial for combating infections during fever. Why would these essential cells perish?
Upon further investigation, the researchers found that not all Th1 cells succumbed; many adapted, altering their mitochondria to become more resilient to stress.
“A wave of stress occurs, resulting in some cell deaths, but those that adapt and survive show increased proliferation and cytokine production,” Rathmell observed.
Heintzman characterized the cellular responses to elevated temperatures at a molecular level. He discovered that heat quickly impaired a mitochondrial protein complex called the electron transport chain complex 1 (ETC1), which is crucial for energy production. This impairment triggered signaling pathways leading to DNA damage and the activation of the tumor suppressor protein p53, which helps repair DNA or initiates cell death to protect the genome. Notably, Th1 cells were more vulnerable to ETC1 impairment compared to other T cell types.
The team found that Th1 cells displayed similar molecular changes in sequencing data from patients with conditions like Crohn’s disease and rheumatoid arthritis, lending further credence to the identified signaling pathway.
“We believe this response is a fundamental mechanism through which cells detect heat and manage stress,” Rathmell said. “Temperature levels fluctuate across tissues and over time, yet their precise effects remain largely unknown. If changes in temperature alter cellular metabolism via ETC1, that could have significant implications. This is foundational information that should be in textbooks.”
The research indicates that heat may induce mutations, especially when cells with mitochondrial stress fail to repair DNA damage or undergo cell death.
“Sustained elevated tissue temperatures from chronic inflammation may elucidate how certain cells become cancerous,” Heintzman noted, pointing out that nearly 25% of cancers are associated with chronic inflammation.
Rathmell concluded, “People often inquire whether fever is beneficial or harmful. The simple answer is: a slight fever can be beneficial, while a high fever can be detrimental. We already knew this, but we now have a clearer understanding of the mechanism behind the adverse effects.”
This research was funded by multiple grants from the National Institutes of Health (including R01DK105550, R01HL136664, R01CA217987, R01HL118979, R01AI153167, R01CA245134, T32AI112541, T32DK101003, T32AR059039, K00CA253718), the Lupus Research Alliance, the Waddell Walker Hancock Cancer Discovery Fund, and the National Science Foundation.
