Researchers gain new understanding of how immune cells respond to heat during fever

Study reveals that moderate fever temperatures (39°C) improve metabolism, proliferation, and effector function of CD4 T cells while reducing regulatory T cell suppression.

In a recent study published in Science Immunology, researchers investigated the effects of heat, particularly during a fever, on immune cells.

Background

During an illness, the body frequently develops a fever, indicating inflammation and the body’s defense against pathogens. T cells play a crucial role in defending humans against infections and illnesses. These cells use a distinct metabolic pathway to carry out their duties successfully. However, the impact of heat on immune cells is unclear.

Body temperature may vary throughout immunological responses. In chronic inflammatory illnesses like rheumatoid arthritis, T cells can adapt to higher temperatures, resulting in a heat shock reaction. Temperature affects T cells differently depending on the subset. Studies report that high temperatures can increase the effectiveness of T helper 1 (Th1), Th2, and Th17 cells and improve the activity of cluster of differentiation 8 (CD8)-expressing cytotoxic T cells.

About the study

In the present study, researchers investigated the impact of elevated body temperature on T-cell metabolism and function.

Researchers cultured murine helper T (CD4-expressing) cells at 37°C or 39°C to examine T-cell changes caused by temperature elevation. Ki67 expression in the spleen and mesenteric lymph nodes indicated T-cell proliferation, whereas interferon-gamma levels indicated their function. Phosphorylated protein kinase B (Akt)-mammalian target of the rapamycin C1 (mTORC1) pathway components represented T-cell metabolism. Enzyme-linked immunosorbent assays (ELISA) measured cytokine expression.

The team examined changes in glycolysis and respiration in subsets of T cells at high temperatures. Extracellular acidification (ECAR) indicated glycolysis changes, while basal and maximal oxygen consumption rates (OCRs) and spare respiratory capacity (SRC) evaluated respiratory changes. Researchers also examined alterations in mitochondrial electron transport chain complex 1 (ETC1).

Mitochondrial reactive oxygen species (mitoROS) levels indicated stress and oxidative damage. Superoxide production and H2AX phosphorylation indicated deoxyribonucleic acid (DNA) damage. Th17 and regulatory T cells were grown with metabolic inhibitors to determine their reliance on glutaminolysis and glycolysis.

Researchers used in vitro Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) screening among Th1 cells to determine the molecular basis of cell death. They extracted T cells from wild-type and Trp53^−/− mice and cultured them at 37° and 39°C to assess their viability. The researchers conducted gene expression studies in mice with inflammatory bowel disease (IBD) to investigate whether in vivo inflammation produced comparable stress responses as functional correlations.

T cells transduced with CRISPR libraries underwent adoptive transfer into Rag1^−/− hosts with IBD. Researchers used single-cell ribonucleic acid sequencing (scRNA-seq) datasets from Crohn’s disease and rheumatoid arthritis patients to uncover associations that may indicate temperature variation in human inflammation.

Results

When the body temperature rises to 39°C (moderate fever), murine helper T cells activate. At high temperatures in inflammatory circumstances, helper T cells use more energy (metabolism) to multiply faster and work harder to combat inflammation. In contrast, higher temperatures reduce the effectiveness of regulatory T cells in limiting the growth of cytotoxic T cells.

The heat affects ETC1 and increases oxidative stress in the mitochondria, or energy-producing components of a cell. This lowers cell viability and damages the DNA. The increased stress and DNA damage cause apoptosis or programmed cell death. In this situation, several murine and human Th1 cells, a type of helper T cell, are destroyed.

Some TH1 cells can adapt to heat by expanding their mitochondria. They also boost their ability to repair DNA damage, the genetic material that regulates cell activity. This adaptability allows them to remain healthy and function better at high temperatures. The modified Th1 cells activate interferon and p53 genes. The p53 protein repairs DNA and contributes to genomic integrity. Interferon genes enhance T-cell effector function, or the ability to fight infections.

The increased dependency on glycolysis among regulatory T cells and glutaminolysis among Th17 cells indicate metabolic adaptations to high temperatures. Th17 cells produced more interleukin-17A at the higher temperature. The researchers found similar damage and stress in TH1 cells among individuals with chronic inflammation. The findings showed that the effects of heat on immune cells are not restricted to mice but also occur in humans.

Conclusion

The study findings showed that mild fever may exert beneficial and adverse effects on immune cells. High temperatures increase interferon activity in helper T cells to enhance their activity while damaging regulatory T cells through mitochondrial stress and DNA damage. While many Th1 cells die, some can adapt to high temperatures by increasing mitochondrial mass and p53-mediated DNA repair to function regularly. Understanding the impacts of high temperatures on T cells can help scientists develop more effective treatments for infections and fevers.

Story first appeared on News Medical