T-cell background
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Researchers at the Institute for Systems Biology (ISB) in Seattle have shown that the different disease-fighting functions of distinct T cells are determined by the genetically encoded T-cell receptor (TCR) sequence that are unique to those cells.

T cells, the foot soldiers of the human immune system, play a pivotal role in defending the body against infections and cancers. Until now, unraveling the mystery of how these cells differentiate into specific functional roles has remained a challenge. In a new research paper published in Cell Reports, researchers from the ISB have uncovered that the genetically TCR sequence, established in early childhood, is the primary factor determining the function of a T cell.

Daniel Chen, PhD, first author of the paper, emphasized the importance of the TCR sequence, stating, “It is that receptor sequence—the proteins on the T cell that bind to foreign antigens—that determines what this cell’s phenotype is, and thus determines what its function is going to be.” According to the researchers, this discovery fundamentally alters our understanding of T cell biology by shifting the focus away from signaling proteins like cytokines and blood components to the TCR sequence as the key determinant of T cell function.

To demonstrate the significance of their findings, the ISB research team conducted a clinical study involving 68 patients. The study focused on approximately 700 T cells that specifically interacted with antigens derived from SARS-CoV-2, influenza, or cytomegalovirus. The results of the study not only validate the central role of the TCR sequence but also reveal its potential for customizing immune responses to specific antigens.

James R. Heath, PhD, ISB president and professor and the corresponding author of the paper, underscored the implications of this discovery for T cell cancer immunotherapies. He explained, “T-cell receptor-engineered T cell cancer immunotherapies are an emerging treatment for solid tumors. We know that a successful immune response requires a balance of T cell phenotypes, some of which kill tumor cells, but others which can form memory or perform other functions.” Heath added, “We show that there is basically a card catalog available. If you want to engineer a balanced immune response, you go to that card catalog, you find the particular TCR genes that, when engineered to build the cell therapy, can provide that balanced response.”

This “card catalog” concept is a revolutionary step towards personalizing immune responses for different diseases. The researchers acknowledge that various diseases may require distinct TCR sequences, but many antigens are immunogenic, meaning T cells targeting the same antigen can be shared among different patients suffering from the same disease. As Dr. Chen noted, “This is important because it means that what we learn for one patient is likely going to be applicable for another.”

The researchers believe that the potential applications of this discovery are vast, with implications not only in cancer immunotherapies but also in vaccine development and the treatment of infectious diseases. By leveraging the unique TCR sequences present in T cells, scientists may develop tailored immune responses, potentially revolutionizing the field of personalized medicine.

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