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Nashville, TN – Researchers at Vanderbilt University Medical Center have uncovered critical insights into how elevated body temperatures, such as those experienced during fever, affect immune cells. Their study, published on September 20 in Science Immunology, reveals that while fever enhances the metabolism and activity of immune T cells, it simultaneously induces mitochondrial stress and DNA damage in a specific subset of these cells.
Led by Dr. Jeff Rathmell, the Cornelius Vanderbilt Professor of Immunobiology, the research explores an often-overlooked area regarding temperature’s impact on immune function. While most studies have focused on agriculture and livestock, this investigation provides a clearer mechanistic understanding of cellular responses to heat—insights that could elucidate how chronic inflammation may contribute to cancer development.
“Standard body temperature is not actually the temperature for most inflammatory processes,” noted Rathmell. “Few have really gone to the trouble to see what happens when you change the temperature.”
The impetus for this research stemmed from the personal experiences of graduate student Darren Heintzman, whose father suffered from an autoimmune disease characterized by prolonged fever. Intrigued by the implications of a higher body temperature, Heintzman cultured T cells at 39 degrees Celsius (102 degrees Fahrenheit) and observed significant changes.
The results showed that elevated temperatures increased the metabolism and activity of helper T cells, which are crucial for responding to infections, while suppressing the function of regulatory T cells. However, an unexpected outcome emerged: a subset of helper T cells known as Th1 cells experienced mitochondrial stress and DNA damage, leading to cell death.
“This finding was puzzling since Th1 cells play a key role in fighting infections where fever is common,” Rathmell explained. “Why would these essential cells die?”
Further analysis revealed that while some Th1 cells succumbed to the stress, others adapted, modifying their mitochondria to become more resilient. “There’s a wave of stress, and some of the cells die, but the ones that adapt and survive are better—they proliferate more and produce more cytokines,” Rathmell added.
Heintzman identified specific molecular changes during the fever response, discovering that heat impaired a crucial mitochondrial protein complex known as electron transport chain complex 1 (ETC1). This impairment triggered DNA damage signaling pathways and activated the tumor suppressor protein p53, which is involved in DNA repair or cell death. Notably, Th1 cells exhibited heightened sensitivity to ETC1 impairment compared to other T cell subtypes.
The research team found similar mitochondrial changes in Th1 cells from patients with inflammatory diseases such as Crohn’s disease and rheumatoid arthritis, supporting their findings. “We think this response is a fundamental way that cells can sense heat and respond to stress,” Rathmell said.
The implications of this study are profound. It suggests that prolonged elevated tissue temperatures could contribute to tumorigenesis, linking chronic inflammation to cancer development. Heintzman noted that up to 25% of cancers are associated with chronic inflammation, underscoring the importance of this research.
In addressing the dual nature of fever, Rathmell summarized, “A little bit of fever is good, but a lot of fever is bad. We already knew that, but now we have a mechanism for why it’s bad.”
This groundbreaking study was supported by multiple grants from the National Institutes of Health and other organizations, highlighting the collaborative effort in advancing our understanding of immune responses to temperature variations.
As fever is a common symptom of infection and inflammation, these findings pave the way for new therapeutic strategies that could mitigate the adverse effects of prolonged elevated temperatures on immune cells, ultimately contributing to better health outcomes in patients with chronic inflammatory conditions.
