Transplantation tolerance related to the susceptibility of conventional T cells to Treg suppression

Transplantation tolerance related to the susceptibility of conventional T cells to Treg suppression

Patients who receive an organ transplant must take strong medications to prevent the immune system from rejecting the organ. Unfortunately, these medications can cause a variety of serious side effects and increase the risk of viral and bacterial infections. Therefore, researchers continue to look for ways to allow the immune system to accept a new organ while maintaining its normal functions.

In a new study published this week in the Proceedings of the National Academy of Sciences, University of Chicago researchers showed that in a model of mice with complete transplant tolerance, immune T cells that would normally attack the transplanted organ are more susceptible to suppression by regulatory T cells because they downregulate the expression of a key transcription factor. The research explains a new mechanism that explains why some animals rejected transplants while others achieved full acceptance, which could represent a potential target for improving transplant survival rates in humans.

The mice used in these experiments received a short-term treatment called costimulation blockade, which allowed them to permanently accept a heart transplant without having to continue taking immunosuppression drugs. Maria Luisa-Alegre, MD, PhD, professor of medicine at UChicago, and Anita Chong, professor of surgery at UChicago, co-senior authors of the new study, wanted to delve deeper into what was going on in these mice to help them tolerate the new organ so well.

If we succeed in achieving transplant tolerance in mice, we want to understand when this happens and how the immune system changes. And if we understand this, we may be able to develop new therapies to achieve transplant tolerance in humans too.”

Maria Luisa-Alegre, MD, PhD, Professor of Medicine, UChicago

T cells help the immune system fight infections and other foreign invaders. They come in many different flavors, including CD4+ T cells, which coordinate the immune response by stimulating other immune cells such as macrophages, B cells, and other types of T cells. There are two additional subgroups among CD4+ T cells; Conventional T cells help other immune cells, while regulatory T cells (commonly known as Tregs) shut down the conventional T cells at the end of an immune response.

Normally, these cells work together to first boost the response to a virus or pathogenic bacteria and then smoothly shut down once the infection has cleared. Unfortunately, these cells also recognize a transplanted organ as a foreign invader and respond in the same way. Therefore, scientists are trying to figure out how to prevent this reaction to a transplant without having to suppress the entire immune system indefinitely.

A few years ago, Alegre and her team collected transplant-specific conventional T cells from mice that accepted heart transplants and sequenced their RNA. This would allow them to see which genes were active and expressed, potentially providing an indication of how the mice were able to tolerate the new organ. They eventually focused on a gene known to play a role in the immune response to cancer tumors: a transcription factor called Satb1. In the cancer response and in the rejection of a transplanted organ, this gene is upregulated or more highly expressed, but in the transplant-tolerant mice it was downregulated, meaning it was expressed less.

“That made sense because what we want to achieve in transplant versus cancer is a mirror image,” Alegre said. “Cancer researchers try to boost the immune system to fight off cancer, but we want to shut down the immune system so the transplants don’t get rejected.”

They initially thought that the downregulated Satb1 would impair the function of conventional T cells, which explains why these mice accepted the transplants, but it turned out it wasn't that simple. They tested another group of mice in which Satb1 was knocked out in conventional T cells, rendering it non-functional, and hoped that this would enable these mice to accept transplants. But they also rejected new organs, just like mice with intact Satb1. However, when the researchers added a small number of Tregs, the mice accepted the organ. This suggested that although the conventional T cells functioned properly in both cases, the lack of Satb1 made them more susceptible to being knocked out by Tregs.

Alegre said this finding is still a long way from being translated into new treatments for humans, but it gives them insight into exactly what transplant tolerance looks like at the immune cell level. Perhaps one day this could be incorporated into a new, more precise immunosuppression regimen.

"It reveals two things. One thing was not known, which is that a transcription factor increases or decreases the susceptibility of conventional T cells to suppression by Tregs," she said. “And second, it reveals another component of transplant tolerance that we may be able to exploit to make transplant tolerance more robust.”

Source:

University of Chicago

Reference:

Gupta, PK, et al. (2022) Reduced Satb1 expression predisposes conventional CD4+ T cells to Treg suppression and promotes graft survival. PNAS. doi.org/10.1073/pnas.2205062119.