Researchers at Children’s Hospital of Philadelphia (CHOP) have made a significant breakthrough, identifying a crucial metabolic process within cells that orchestrates rapid immune responses. Their findings, published in the journal Science Immunology under the title “Single-cell NAD(H) levels predict clonal lymphocyte expansion dynamics,” shed light on why immune cells adept at recognizing pathogens, vaccines, or diseased cells proliferate more rapidly than others, potentially impacting cancer treatment and vaccine development strategies.
Antigens, foreign substances recognized by our immune system, trigger the production of T and B cells. These cells possess unique receptors capable of identifying specific antigens, allowing them to mount tailored responses and exhibit memory upon subsequent exposure to the same antigen.
The affinity of T and B cells for their respective antigens, a pivotal concept in immunology, determines their responsiveness. Vaccines exploit this principle by priming the immune system with antigens, prompting high-affinity cells to proliferate rapidly to combat future encounters with the same antigen.
Despite the critical role of high-affinity immune cells in effective immune responses, the underlying mechanisms driving their enhanced proliferation have remained elusive. Researchers sought to unravel this mystery by investigating cellular metabolism, hypothesizing that metabolic changes could signal high-affinity cells to proliferate more vigorously.
Senior study author, Will Bailis, Ph.D., Assistant Professor of Pathology and Laboratory Medicine at CHOP and the Perelman School of Medicine of the University of Pennsylvania, led the investigation. The team identified nicotinamide adenine dinucleotide (NAD) as a pivotal metabolite dictating T cell receptor metabolic reprogramming during early T cell activation stages.
Utilizing flow cytometry, the researchers assessed NAD levels in single cells post-activation, linking NAD abundance to the proliferative capacity of T cells. This insight allowed them to predict T cell behavior and division frequency based on initial NAD levels.
Moreover, manipulating cellular NAD production influenced the transition from quiescence to proliferation, suggesting the potential use of NAD modulation in enhancing T cell-driven therapies and vaccines.
Bailis emphasized the significance of single-cell metabolic differences in driving diverse cellular behaviors, offering insights into disease mechanisms beyond conventional gene regulation or signaling pathways. The team envisions leveraging this knowledge to refine vaccine strategies and optimize the efficacy and durability of cell-based therapies for cancer and other diseases.
