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Researchers plan metabolic signaling machines to produce memory T cells

The discovery of the metabolic pathways that inhibit the production of memory T cells has the potential to boost the immune system’s ability to fight infections and cancers.

Credit: St. Jude Children’s Research Hospital

Immunologists at St. Jude Children’s Research Hospital have mapped the previously unknown biological mechanism by which the immune system generates T cells that kill bacteria, viruses and cancer cells.

The results have multiple implications for how the adaptive immune system responds to infection to generate memory T cells. Experiments have revealed mechanisms that inhibit the growth of long-lived memory T cells that are constantly replenished to protect the body over time. Blocking these inhibitory mechanisms with pharmacological or genetic approaches can enhance protective immunity against infections and cancers.

The researchers also discovered a subtype of memory T cells that they called the end effector precursor cells. Mapping the pathway that controls these cells raises the possibility of manipulating this pathway to boost the immune system’s ability to kill microbes and cancer cells.

The control pathway mapping also introduced the idea that the diet may have a greater effect on immune function than previously thought.

Led by Hongbo Chi, Ph.D., from the Department of Immunology, the research appears today in the journal cell. The early authors are Hongling Huang, Ph.D. And Bibi Zou, Ph.D., is in immunology.

CRISPR-assisted mapping of the metabolic mechanism

When the body encounters an infection, the immune system begins to produce T cells that respond to attacking the invading bacteria or viruses. There are two types of these T cells. One type is memory precursor cells, which can develop into memory T cells that last for a long time to protect the body. These are the T cells that are produced by vaccines. The second type is short-lived peripheral effector T cells, which have immediate cytotoxic activity.

In this study, researchers sought to determine the metabolic mechanism that controls the way the immune system decides to produce memory T cells. Chi and colleagues focused on the unknown mechanisms that prevent the generation of this type of T cell.

The scientists used a gene-manipulating technique called CRISPR to examine more than 3,000 genes that control metabolism in mouse cells. The goal was to discover genes that regulate the “fate” of effector T cells and memory T cells.

Nutrients play an unexpected role in the fate of T cells

The research revealed a previously unknown role that nutrients, such as amino acids and some sugars, play in regulating T-cell fate. To the researchers’ amazement, the analysis identified pathways related to the nutrients that suppress the production of memory T cells.

“The preconceived idea of ​​the role of nutrients in immune cell function was that cells depend on nutrients as a source of energy and as building blocks,” Huang said. But our study offers another view – that nutrients have a role in inhibitory pathways, and that deprivation of certain nutrients or metabolites may be beneficial for adaptive immunity.

“It seems to indicate that what you eat and drink may have a greater effect on immune function than previously expected,” Huang said. “This will be an important path of research in the future.”

A new T cell subtype has been identified

Studies also revealed a new subtype of effector T cells, which they named the end effector precursor cells. Blocking the development of these cells may be key to boosting T-cell-mediated immunity. The researchers’ work identified a pathway that controls the transition of developing T cells from the intermediate stage to the mature terminal effector primary cells.

The researchers found that they could manipulate this pathway to keep the end effector primary cells in this intermediate stage that would stimulate them to proliferate to produce more memory T cells. “These results highlight the possibility of targeting this pathway to enhance protective immunity against infections and tumors,” Chi said.

“We are very excited about these results,” Chi said. “By defining this nutrient signaling axis, our studies provide new biological insights and treatment targets to enhance memory T cell responses and protective immunity against pathogens and tumors.”

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The other authors are Jun Wei, Lingyun Long, Hao Shi, Yogesh Dhungana, Nicole Chapman, Guotong Fu, Jordy Saravia, Jana Raynor, Shaofeng Liu, Gustavo Palacios, Yong-Dong Wang, Chenxi Qian, and Jiyang Yu of Saint Jude.

The research was supported by the National Institutes of Health (AI105887, AI131703, AI140761, CA176624, CA221290) and ALSAC, St. Jude’s fundraising and outreach organization.

St. Jude Children’s Research Hospital

St. Jude Children’s Research Hospital leads the way the world understands, treats and treats childhood cancer and other life-threatening diseases. It is the only National Cancer Institute designated comprehensive cancer center that is exclusively for children. Treatments developed at St. Jude’s Hospital have helped increase the childhood cancer survival rate from 20 percent to 80 percent since the hospital opened more than 50 years ago. Saint Jude freely shares her breakthroughs, and every child saved in Saint Jude means that doctors and scientists around the world can use this knowledge to save thousands of other children. Families never receive a bill from St. Jude for treatment, travel, housing and food – because every family has to worry about helping their children survive. To learn more, visit stjude.org or follow St. Jude on social media at stjuderesearch.

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