Metabolic Insights into Immune Cell Activation and Response

Researchers from Children's Hospital of Philadelphia (CHOP) identified a key metabolite in cells that helps direct immune responses and explains at a single cell level why immune cells that most efficiently recognize pathogens, vaccines, or diseased cells grow and divide faster than other cells. The findings also indicate that a better understanding of this metabolite and its role in immune response could improve the design of immunotherapies and create longer-lived responses against different types of cancer as well as enhance vaccine strategies. The findings were published online today by the journal Science Immunology.

Antigens are foreign substances that our immune system recognizes and responds to by producing more T and B cells. These cells each have unique receptors that recognize specific antigens and can respond appropriately, and they can "remember" and respond similarly when exposed to the same antigen again. How well a T or B cell to sees its antigen is known as its affinity. This fundamental concept of immunology is how vaccines work. When those T and B cells encounter a pathogen, the body needs the ones that recognize their antigen the best, with high affinity, to divide more quickly to produce more daughter cells and "attack" the invader.

However, the underlying mechanisms as to why high affinity immune cells respond more efficiently have remained a mystery for researchers. After seeing an antigen, the chemistry inside T and B cells needs to change to allow them to properly respond. The researchers in this study wanted to look at metabolism to understand what causes high affinity cells to know that they need to divide more quickly to respond appropriately.

We wanted to see if specific metabolites were sensitive to T cell receptor affinity and controlled T cell expansion during immune responses."

Will Bailis, PhD, Senior Study Author, Assistant Professor of Pathology and Laboratory Medicine at CHOP and the Perelman School of Medicine of the University of Pennsylvania

The researchers identified nicotinamide adenine dinucleotide (NAD) as a key, affinity-dependent component of T cell receptor metabolic reprogramming during the early stages of a T cell activation. Using flow cytometry, the researchers could look at NAD in single cells immediately after activation and show how it dictates the number of times T cells can divide in the future. Therefore, researchers could essentially predict how T cells behave and how many times they divide based on how much NAD they started with.

Additionally, the researchers found that manipulating how much NAD a cell was allowed to make could control when that cell went from a resting state to wanting to divide, suggesting that the metabolite could be used to improve response in certain T cell-driven therapies or vaccines.

"We believe this work shows how single cell differences in metabolism are a key reason why similar cells sometimes display strikingly different behaviors and that this may provide insight into underlying processes that drive disease and dysfunction that cannot simply be explained by gene regulation or signaling," Bailis said. "With more work, we also believe that this information could potentially be used to improve vaccine strategies and the response and durability of cell-based therapies used 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 of Philadelphia Cell and Gene Therapy Collaborative SEED Award, a Children's Hospital of Philadelphia 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.