MEDICINE AND HEALTH

Who knows! The “heart” of cancer cells


Since the discovery of T cells, their recognition mechanism has been a central question in immunology research.

How do T cells detect the “inner” changes of cancer cells? On September 6, Nature published an important breakthrough in immunology completed by the team of Professor Zhang Yonghui of Tsinghua University and the team of Professor Guo Ruiting of the School of Life Sciences of Hubei University. They revealed the immune recognition mechanism of γδT cells, which brought new prospects for immunotherapy and vaccine development.

Another type of “mysterious” recognition mechanism of T cells

“I started paying attention to this 20 years ago.” At 11 o’clock at night, Zhang Yonghui had not left the office of Tsinghua University’s School of Pharmacy. This is the norm in his work.

In 2003, Zhang Yonghui began to study metabolic pathways related to γδT cells in the United States. He introduced that the immune system is an important mechanism for the human body to resist external bacteria and viruses and protect the normal operation of the body. Among them, T cells are one of the most important components of the immune system, playing an important role in recognizing the “alien self”, sending warning signals, and activating the immune mechanism. Alpha T cells and γδ T cells are two types of T cells.

After phosphine antigen crosslinks the BTN3A1 and BTN2A1 intracellular domains, it induces epitope exposure in the extracellular domain, thereby effectively binding to TCR. Photo courtesy of interviewee

Among them, the recognition mechanism of αβ T cells won the Nobel Prize twice in 1980 and 1996. However, the immune recognition mechanism of another type of T cell, γδ T cells, has not been fully understood.

Zhang Yonghui told China Science News that the immune recognition mechanism of αβ T cells has become a set of classical theories. Recognition of “alien self” by αβ T cells relies on compatible complex proteins (MHCs) on the surface of target cells—pathogens or tumor cells. The peptide antigen is able to anchor to the extracellular segment of the MHC, thereby interacting with the αβ T cell receptor and initiating the activation of αβ T cells.

“The understanding of the recognition mechanism of αβ T cells has laid the theoretical foundation for many medical technologies, including vaccination, autoimmune disease treatment and tumor cell therapy.” However, the recognition mechanism of γδT cells is very unique, and its recognition of the “alien self” does not pass through MHC or rely on peptide antigens, Zhang said. “In-depth understanding of the biological mechanisms of γδT cells is expected to expand the application field of medical technology and move away from the traditional framework of αβ T cells.”

“Scientific cognition needs to be accumulated, not achieved overnight.” Zhang Yonghui said that the study of the recognition mechanism of γδT cells has taken a long time.

It wasn’t until the 90s that scientists slowly discovered that gamma delta T cells could respond to tumors or pathogens because phosphorus antigens could be produced inside these “alien” cells. Phosphorus antigens can activate the largest class of γδT cells in the human peripheral blood.

However, how T cells on the outside of the target cell perceive the phosphorus antigen hidden inside, that is, the changes in the “heart” of the target cell, is difficult to understand.

It wasn’t until around 2010 that the scientific community began to focus on the important role of a transmembrane protein, BTN3A1.

At this time, Zhang Yonghui returned to Tsinghua University to establish his own research group, explore the regulation of metabolism on immunity, and proposed that “isoprene-like”, the most conservative and extensive metabolic pathway in nature, has a profound and long-term impact on immunity.

“Phosphorus antigens are actually starting materials or intermediates for lipid products such as isoprenoids.” Zhang Yonghui said that since then, scientists have gradually discovered the “puzzle” of phosphorus antigens to stimulate the immune mechanism.

It has been studied “biased” by classical theory

“The target cell transmembrane protein BTN3A1 acts on γδT cells in the same way MHC does on αβT cells.” However, Zhang Yonghui said, “antigen binding to the extracellular segment of MHC and activating T cells” is a “classical” understanding of the recognition mechanism of αβ T cells in the field of immunology, which also misleads some scholars to make “formal” mistakes in the recognition pattern of γδT cells.

In 2013, a study published in Nature Immunity showed that phosphorus antigens activate T cells by binding to the extracellular segment of the transmembrane protein BTN3A1 on target cells. Although this mechanism is similar to the way traditional peptide antigens activate αβT cells by binding to the extracellular segment of MHC molecules, it is inconsistent with the production of phosphorus antigens inside target cells, raising questions in the academic community.

In 2019, Zhang Yonghui’s team explored the crystal structure of the transmembrane protein BTN3A1. Yang Yunyun, the first author of the thesis who was still studying for a doctoral degree in Zhang Yonghui’s team at that time, confirmed through structural biology experiments that the intracellular segment of BTN3A1 is the site of phosphorus antigen binding. This result, published in the journal Immunology, resolved a long-standing academic controversy.

But this also brings difficulties to understanding – since the binding site is inside the target cell, how can γδT cells recognize antigen changes inside the target cell?

“I originally studied chemistry and switched to immunology.” Therefore, Zhang Yonghui is sensitive to the interaction between molecules. This helped him develop an important idea.

“Because γδT cell receptors are extremely sensitive to the perception of tumors and pathogens, the binding strength of phosphorus antigen to BTN3A1 is far less than efficient activation of γδT cells.” Zhang’s team therefore speculated that there was an “immune partner” of BTN3A1 in the process—perhaps a protein that had not yet been discovered.

There are thousands of transmembrane proteins, and it is easy to screen.

Yang Yunyun joined Guo Ruiting’s team to continue related research, and Yuan Linjie, who was studying for a doctorate, took over the baton. In the face of difficulties, gritting your teeth must also go on, that is, screening proteins one by one.

After a long screening and research, Yuan Linjie finally found the mysterious “immune partner”, that is, BTN2A1, which is very similar to BTN3A1, just like a pair of “twins”.

At this time, they are more confident and ready to continue their efforts to understand the entire identification mechanism before publishing papers.

However, the unexpected happened. In 2020, Australian scientists were the first to report similar findings in the journal Science and clarified that the extracellular segment of BTN2A1 binds directly to γδT cell receptors.

Upon learning the news, the team members were devastated.

After calming down, Zhang Yonghui encouraged everyone to cheer up. Because the discoveries of Science prove that their hypotheses and research ideas are correct. At the same time, what Science reported has not fully explained how the binding of the intracellular segment occurs, how it leads to the activation of T cells by the extracellular segment, and how the two transmembrane proteins “work together”…

There are still unsolved mysteries and room for this question, and it must be persevered.

“Molecular glue” in immunology

“Intracellular is the initiation of phosphorus antigens, and the role of transmembrane ‘twin’ proteins must be inseparable from intracellular research.” Zhang Yonghui said.

Late on the night of September 6, the paper was officially online, and Zhang Yonghui posted such a circle of friends: This research exhausted the power of the laboratory. Starting with CRISP-CAS9 screening, from humans to alpacas, this nature article covers 6 single-cell atomic force microscopy tests, 12 crystal structure acquisition, 13 chemical synthesis of phosphorus antigens, 39 ITC studies, 39 Chimeric engineering, multiple MD calculations, countless immunological experiments and other biophysical tests.

Through multiple techniques, they showed in detail how phosphorus antigens act like “molecular glue” to promote the tight binding of BTN3A1 to BTN2A1 inside the target cell.

The discovery of the natural phenomenon “molecular glue” has been around for more than 30 years. Zhang Yonghui introduced that as the name suggests, the function of glue is adhesion, American scientist Stuart L Schreiber discovered 30 years ago that cyclosporine can pull two originally unrelated proteins together. This is where the concept of molecular glue comes from.

But few people have applied the concept of “molecular glue” in immunology before. This time, it was still the chemistry knowledge learned in the early years that found the perfect explanation for their team. 

BTN3A1 and BTN2A1 often accompany each other, their extracellular sites are bound together, and the intracellular sites are separated from each other. When the phosphorus antigen pulls the two parts of the cell together like glue, the extracellular binding parts that were originally next to each other are opened.

After separation, “free” BTN3A1 binds to gdT cells simultaneously with BTN2A1. “The power of individuals is effective, and the power of cooperation is powerful.” Zhang said that the two proteins are involved in the capture of phosphorus antigens and the activation of gdT cells, a finding that perfectly explains the “super” immune surveillance ability of gamma delta T cells – that is, under the synergistic effect of the two proteins, even in the presence of small amounts of phosphorus antigens, it can be efficiently “locked”.

Chinese New Year’s Eve the lunar calendar, Zhang Yonghui submitted his paper to the journal Nature. The sound of firecrackers on the first day of the new year woke him up, and when he turned on his computer, he received an email that his paper had been submitted for review.

A month later, the reviewers returned, with two reviewers giving high praise and another reviewer making a number of requests for revisions. The revised draft was sent back 3 months later, and they were stuck in a long wait.

The paper has not yet been confirmed for publication, but Zhang reported their work at the International Conference on γδT Cells in Lisbon in June. The informative and wonderful presentation was recognized by immunology peers.

“Maybe that report gave my peers an idea of how I look at immune recognition from a chemical perspective.” Zhang Yonghui said that soon the paper was accepted.

“The recognition of phosphorus antigens by T cells has brought new ideas to vaccination and the treatment of autoimmune diseases.” Zhang Yonghui said that a cancer cell almost corresponds to a peptide antigen. In cancer treatment and vaccine development, traditional therapies using αβ T cells require “customized” regimens for diverse peptide antigens. However, there is only one phosphorus antigen produced in the cell, so it is easier to identify.

However, he emphasized that because phosphorus antigens are unstable, easy to hydrolyze, and “poor druggability”, it can be considered to replace phosphorus antigens with a drug molecule to achieve the function of molecular glue, so that γδT cells can efficiently recognize and attack tumor cells and infected cells.

“Hopefully, our work will open the door to cognitive dust and usher in a new dawn of immunotherapy.” Zhang Yonghui said. (Source: Li Chen, China Science News)

Related paper information:https://doi.org/10.1038/s41586-023-06525-3



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