Fatty Acids Found to Influence Immune Defense During Chronic Infections

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• Mario Aguilera- [email protected]

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Our immune system implements an array of strategies to combat threatening infections.

White blood cells called cytotoxic T lymphocytes or "CD8 T cells" are soldiers of the immune system, serving as defensive agents that fight invading pathogens. Their role is vital for counteracting short-term, acute viral infections and controlling long-term infections. But every bodily system has its limits. When CD8 T cells reach the point of exhaustion, their protective capabilities decline and the immune system is much less effective.

While the cell's internal driving forces that lead to CD8 T exhaustion have been carefully studied, related external factors that surround and shape these functions are much less understood.

University of California San Diego immunologists have now studied the influences related to metabolism and the environment surrounding CD8 T cells. Their study led to intriguing new insights on the role of fatty acids in chronic infections and other persistent conditions, such as tumors.

"This work highlights how changes in the body's metabolic environment can influence immune function during a prolonged viral infection," said Professor Elina Zúñiga of the Department of Molecular Biology (School of Biological Sciences) and senior author of the study. "It also provides a valuable resource for future studies aimed at understanding how nutrients and other small molecules might be used to fine-tune immune responses in chronic diseases, including persistent viral infections."

The research, led by former UC San Diego graduate student Katelynn Kazane, focused on metabolites, including small molecules such as amino acids, sugars and lipids, in mice that play key roles in metabolism and its many functions and pathways. The study examined how such metabolites circulating in the blood change during short-lived or long-lasting viral infections.

They discovered that an ongoing viral infection causes a brief but striking shift in the availability of nutrients in the early stages after infection. They saw levels of fatty acids increase during the first week after infection, associated with infection-induced changes in eating behavior and fat breakdown.

At the same time, a special group of exhausted CD8 T cells with stem-like properties was found to absorb and store more fat than other T cells. These cells were able to use fatty acids as an energy source to power their mitochondria, the cell's energy producers. When fatty acids were provided later during chronic infection, the number of stem-like T cells expanded.

"This shows that fatty acids can shape different types of exhausted T cells in distinct ways," said Zúñiga.

The results of the study provide new perspectives on sickness-related factors, some of which aren't cleanly classified as "good" or "bad." The study shows that physiological changes that accompany the loss of appetite linked with sickness are unpleasant, but behind the scenes our immune system may be using metabolic changes to bolster a key long-term response.

"What fuels the immune response has always been a hot topic for researchers, but our study focused on a phenomenon that is largely thought of as a negative symptom - an individual gets seriously ill and therefore loses their appetite. It turns out that there may be a biological purpose for what was considered a negative side effect," said Kazane, who received her PhD in Biological Sciences in 2024 and is now a postdoctoral scholar at UCLA.

"These findings highlight the potential role of fatty acids in fine-tuning CD8 T cell subsets and offer a valuable resource for studying other metabolic signatures during viral infections," the authors conclude in their paper.

The study, "Metabolomic profiling reveals the potential of fatty acids as regulators of exhausted CD8 T cells during chronic viral infection," was published in the Proceedings of the National Academy of Sciences. The authors are Katelynn R. Kazane, Lara Labarta-Bajo, Dina R. Zangwill, Kalle Liimatta, Fernando Vargas, Kelly C. Weldon, Pieter C. Dorrestein and Elina I. Zúñiga. The research was funded by the National Institutes of Health (AI081923, AI135314 and AI113923); a UC San Diego Center for Microbiome Innovation seed grant; and a UC San Diego T32 training grant.