To study immune cells, we must take into account their environment

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Living organisms use energy in a radically different way than immune cells in vitro.

For years, scientists have used cells grown in Petri dishes to study the metabolic processes that fuel the immune system. But a new article suggests that living organisms use energy in a radically different way from immune cells in vitro.

The scientific consensus since Warburg's work is that immune cells, called T cells, convert glucose into energy to fuel cellular function. In fact there are different mechanisms by which a cell can get energy, the so-called metabolism or also respiration.

How do the cells get energy?

On the one hand, we distinguish anabolism, which represents all the biosynthetic pathways of cellular constituents, and on the other hand, catabolism, which represents all the pathways of degradation of these cellular constituents into small molecules to release them. energy by oxidation or to rebuild other cellular constituents.

Catabolism can be differentiated between aerobic and anaerobic respiration. Aerobic respiration includes glycolysis, oxidative decarboxylation of pyruvate, citric acid cycle, oxidative phosphorylation.

The main degradation pathway is glycolysis, where sugars such as glucose and fructose are converted to pyruvate and generate ATP. Pyruvate is an intermediate in several metabolic pathways, but the majority is converted to acetyl-CoA by aerobic glycolysis (with oxygen) and introduced into the citric acid cycle.

Lipids are catabolized by hydrolysis to free fatty acids and glycerol. Glycerol enters glycolysis and the fatty acids are decomposed by beta-oxidation to release acetyl-CoA, which is then introduced into the citric acid cycle.

There are two important microbial methane formation pathways, by carbonate reduction (respiration) and acetate fermentation.

Warburg hypothesized that cancer growth is caused by energy-generating tumor cells (such as, for example, adenosine triphosphate / ATP) primarily through anaerobic degradation of glucose (called fermentation or anaerobic respiration). This contrasts with healthy cells, which primarily generate energy from the oxidative decomposition of pyruvate. Pyruvate is a final product of glycolysis and is oxidized in mitochondria. Therefore, according to Warburg, cancer should be interpreted as mitochondrial dysfunction.

For multicellular organisms, during brief periods of intense activity, muscle cells use fermentation to supplement ATP production from slower aerobic respiration.

What was discovered?

Jones and colleagues found that T cells in a living system use glucose as a building block for DNA replication and other maintenance tasks, in addition to converting glucose into raw energy. They also discovered that the way T cells treat glucose evolves during an immune response. The metabolism of glucose in T cells changes dynamically during an immune response. Glucose-dependent serine biosynthesis promotes T-cell proliferation in vivo.

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This suggests that T cells can use resources differently in the body when they are fighting a bacterial infection such as Listeria or a disease like cancer.

Naïve CD8+ T cells differentiating into effector T cells increase glucose uptake and transition from resting metabolism to anabolic metabolism. Although much is known about the metabolism of cultured T cells, the way in which T cells utilize nutrients during the in vivo immune response is less well defined. The researchers therefore combined the bioenergetic profiling and 13C glucose perfusion techniques to study the metabolism of CD8+ T cells responding to Listeria infection.

In contrast to the in vitro activated T cells, which exhibit Warburg metabolism, physiologically activated CD8+ T cells exhibited higher levels of oxidative metabolism, higher bioenergetic capacity, differential pyruvate utilization, and high 13C carbon flux. glucose to the anabolic pathways, including the biosynthesis of nucleotides and serine. The glucose-dependent serine biosynthesis induced by the Phgdh enzyme was essential for the expansion of CD8+ T cells in vivo.

Our immune cells do not work in isolation

"It's like watching animal behavior in a zoo or in the wild - our immune cells do not work in isolation - they work with a host of other cells and factors that influence how and when they are used. of energy, "said Russell Jones, Ph.D., lead author of the study and head of the Metabolic and Nutritional Programming Group at the Van Andel Institute. "Understanding cell metabolism is a crucial part of therapeutic development, and our results reinforce the need to study these cells in an environment as close as possible to nature."

The findings have profound implications for how scientists study the complex and interconnected systems that underlie health and disease and how they translate this information into new diagnostic and treatment strategies.

"Immune cells react much more dynamically to infections and diseases than we previously thought," Jones said. "For a while, we're at a stage of metabolism research, it's like we're in the dark under a lamppost, we could only see in front of us, and these results will help us better understand this. which immune cells need for optimal function. "

Which suite will be given?

The results were made possible by a new method developed in consultation with collaborator Ralph DeBerardinis, MD, Ph.D., who allowed Jones and his colleagues to map how T cells use nutrients in living organisms. They have developed a 13C infusion method to study T cell metabolism in vivo

"In the future, this new mapping technique will be invaluable in pursuing studies of specific diseases," said Eric Ma, Ph.D., lead author of the study and a postdoctoral researcher in the field. Jones's laboratory.

In the future, the team plans to design human studies to measure how T cells use glucose and other nutrients when they respond to pathogens or other diseases such as injuries or diseases such as cancer.

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