St. Jude Children’s Research Hospital and Fred Hutchinson Cancer Research Center have developed an algorithm that predicts T cell recognition of antigens and sets the stage to more effectively harness the immune system.
Scientists from St. Jude Children’s Research Hospital and Fred Hutchinson Cancer Research Center have developed an algorithm that functions like a Rosetta Stone to help decipher how the immune system recognizes and binds antigens.

The research, which appeared as an advance online publication in the journal Nature, should aid development of more personalized cancer immunotherapy and advance diagnosis and treatment of infectious diseases.

The immune system depends on molecules called T cell receptors on the surface of T cells to recognize and respond to foreign antigens from virus–infected cells, tumors and other threats. Genomic rearrangement means that a large number of different T cell receptors are possible. Each person can have about 100 million different receptors, referred to as their T cell repertoire, with little overlap even in identical twins. Each receptor in the repertoire is capable of recognizing a different antigen and rallying the immune response to address that threat.

“Until now, this amazing diversity has thwarted efforts to categorize T cell receptors that recognize and respond to the same antigen,” said Paul Thomas, PhD, an associate member of the St. Jude Department of Immunology. He and Philip Bradley, PhD, of Fred Hutchinson Cancer Research Center and the University of Washington in Seattle, are co–corresponding authors of the research.

“That has hampered not only understanding of immune recognition but also our ability to use the immune system more effectively to target new viruses or mutations driving tumor cells,” Thomas said. “With this algorithm we have a system to identify critical features of T cell receptors that recognize the same antigen and how they interact. That lays the groundwork for designing receptors to recognize cancer or new viruses.”

The algorithm was built using tools the researchers developed to define how T cell receptors recognize a part of the antigen called the epitope. Epitopes are displayed on the surface of circulating immune cells and are where T cells bind antigens to fuel the immune response. Multiple epitopes are produced from the same virus, tumor or other threat. Each epitope is targeted by a pool of T cells bearing different, but specific, T cell receptors to recognize and respond.

The tools included TCRdist, which researchers used to calculate the similarity and differences of key features of T cell receptors, such as amino acid sequences in important regions for antigen recognition. TCRdist allowed the scientists to identify T cell receptors that recognized the same epitope.

“These analytical tools helped us to understand the T cell repertoire against a particular antigen in a more coherent way than we have been able to do before. Grouping T cell receptors for a given epitope revealed underlying common features that characterized the bulk of the repertoire,” said first author Pradyot Dash, DVM, PhD, a staff scientist in Thomas’ laboratory.