Newswise – Philadelphia, March 15, 2024 – researchers Children’s Hospital of Philadelphia (CHOP) identified a key metabolite in cells that helps direct immune responses and explains at the single-cell level why immune cells that most efficiently recognize pathogens, vaccines or diseased cells grow and divide faster than other cells. The results also suggest that a better understanding of this metabolite and its role in the immune response could improve the design of immunotherapies and produce longer-lasting responses against various cancers, as well as improve vaccination strategies. The results were published online today by the journal Scientific immunology.

Antigens are foreign substances that our immune system recognizes and to which it responds by producing additional T and B cells. These cells each have unique receptors that can recognize specific antigens and respond accordingly. They can “remember” and respond similarly when exposed to the same antigen again. How well a T or B cell recognizes its antigen is called affinity. This fundamental concept of immunology describes how vaccines work. When these T and B cells encounter a pathogen, the body needs the cells that best recognize its antigen and with high affinity to divide faster, produce more daughter cells and “attack” the invader.

However, the underlying mechanisms why high-affinity immune cells respond more efficiently remain a mystery to researchers. After an antigen is seen, the chemistry in the T and B cells must change so they can respond properly. The researchers in this study wanted to examine metabolism to understand what causes high-affinity cells to know that they need to divide faster to respond appropriately.

“We wanted to see whether certain metabolites are sensitive to T cell receptor affinity and control T cell expansion during immune responses,” said the lead study author Will Bailis, PhDAssistant Professor of Pathology and laboratory medicine at CHOP and the Perelman School of Medicine at the University of Pennsylvania.

The researchers identified nicotinamide adenine dinucleotide (NAD) as an important affinity-dependent component of the metabolic reprogramming of T cell receptors in the early stages of T cell activation. Using flow cytometry, the researchers were able to study NAD in individual cells immediately after activation and show how it determines the number of T cell divisions in the future. Therefore, researchers could essentially predict how T cells would behave and how often they would divide based on the amount of NAD they started with.

In addition, the researchers found that by manipulating the amount of NAD a cell is allowed to produce, it is possible to control when the cell goes from resting to dividing, suggesting that the metabolite can be used to improve the response at certain T- Cell-controlled therapies or vaccines could be used.

“We believe this work shows that differences in the metabolism of individual cells are a key reason why similar cells sometimes exhibit strikingly different behaviors, and that this may provide insights into underlying processes that drive disease and dysfunction that cannot simply be caused by Gene regulation or signal transmission can be explained,” said Bailis. “With more work, we also believe this information could potentially be used to improve vaccination strategies as well as the response and durability of cell-based therapies to treat cancer and other diseases.”

This study was supported by National Institutes of Health Grants K22AI141758, R35GM138085, R01DK098656, R01HL165792, P30ES013508, R01AI165706, and F31CA261156, a children’s hospital and a children’s hospital, a children’s hospital and a children’s hospital, a children’s hospital and a children’s hospital, a children’s hospital and a children’s hospital, a children’s hospital hospital and a children’s hospital, a children’s hospital and a children’s hospital, a children’s hospital and the Gassen Award, a children’s hospital and the Gassen Award, a children’s hospital and a Gassen Award and a children’s hospital. Junior Faculty Pilot Grant, Transfusion Medicine Research Training Program Grant 2T32HL00777528, Microbial Pathogenesis and Genomics Training Grant 5T32AI141393 and Immunobiology of Normal and Neoplastic Lymphocytes Training Grant T32CA009140.

Turner et al.: “Single-cell NAD(H) levels predict the dynamics of clonal lymphocyte expansion.” Sci Immunol. Online March 15, 2024. DOI: 10.1126/sciimmunol.adj7238.

About Children’s Hospital of Philadelphia:

The Children’s Hospital of Philadelphia, a nonprofit, charitable organization, was founded in 1855 as the nation’s first children’s hospital. Through its longstanding commitment to providing exceptional patient care, training new generations of pediatric professionals and pioneering major research initiatives, the hospital has fostered many discoveries that have benefited children around the world. The pediatric research program is among the largest in the country. The facility has a long history of providing advanced pediatric care close to home CHOP Care Networkwhich includes more than 50 primary care practices, specialty care and surgery centers, urgent care centers and community hospital alliances throughout Pennsylvania and New Jersey the Middleman Family Pavilion and its dedicated pediatric emergency room in King of Prussia. Additionally, its unique family-centered care and public service programs have earned Children’s Hospital of Philadelphia recognition as a leading advocate for children and adolescents. For more information visit https://www.chop.edu.

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