Tissue-resident memory (TRM) T cells, a subset of white blood cells that persist for extended periods of time within tissues, are regarded as a critically important element of the human immune response to cancer and infectious diseases. These weaponized, pro-inflammatory T cells are thought to remain within tissues following an immune response, poised to respond to future insults. However, the mechanisms leading to the generation of TRM T cells are not completely understood.
Researchers from the Instituto de Medicina Molecular Joâo Lobo Antunes of the University of Lisbon in Portugal have discovered that a population of T cells with immunosuppressive properties, known as regulatory T cells, promote the generation of TRM T cells. Their findings have important implications for the development of vaccines and cancer immunotherapies.
“Our work was derived from two previous projects,” senior author Dr. Marc Veldhoen told ImmunoFrontiers. “In 2011 we reported (Li et al., Cell) that T cells present in tissues such as the intestine critically rely on the transcription factor arylhydrocarbon receptor (AhR). We had been working on this factor since we described it in 2008 (Veldhoen et al, Nature). An encounter with the group of Frank Carbone resulted in the additional observation that a third subset of memory T cells, termed tissue resident T cells (Trm) also require the expression of AhR. These cells are generated after an immune response and have the ability to respond very rapidly when the same or similar microorganism is encountered again.”
“To try and understand the role of AhR we studied the metabolic requirements of tissue resident T cells. However, this led us to a complete different path, describing that tissue resident cells have a different energy status (Konjar et al., 2018, Science Immunology). This planted the seed that to become Trm, cells need to reduce the activity of T cells that have initially been activated by the contact with a pathogen. The “suppression” of T cell activity can be achieved by a specialised cell called regulatory T cells (Treg). We hypothesised that Trm may be formed in tissues if a subpopulation of Treg may be present at the same time as the effector T cells. The common factor, we reasoned would be the expression of AhR.”
“To test our hypothesis, we needed a complex system in which T cells can be activated in their normal environment, we can follow their fate and we can genetically alter the presence of factors of potential importance. For this we used the laboratory mouse. We can infect the mice with a mild pathogen and follow the immune response and the generation of Trm cells. To show if AhR expression is important in Treg cells, we removed it specifically and only in Treg cells using the Cre – LoxP system. This is based on the transcription factor Foxp3 which is only expressed in Treg. When this factor is expressed, the Cre enzyme was added in these mice, which can recognise specific DNA sequences called LoxP sites and remove the section these sequences flank. In addition, we have mice in which genes are flanked by LoxP sites, such as AhR.”
“We were quite wrong about AhR. The removal of AhR in Treg cells did not result in any changes in the experiments we performed. We subsequently checked other transcription factors that play a role in Trm cells, using the same methods. Fortunately, it turns out that the transcription factor Tbet is an factor of importance to bring Treg and effector T cells together and facilitates the development of Trm cells. We continued to test some of the factors that Treg cells may contribute to the generation of Trm cells. After excluding some, we could validate Transforming growth factor beta (TGFb) as being important.”
The study, “Type 1 Treg cells promote the generation of CD8+ tissue-resident memory T cells,” was recently published in the journal Nature Immunology and may support the development of the next generation of vaccines and cancer immunotherapies.
“Trm cells are important to patrol our external barriers, those sites where we are most exposed and at risk to encounter a pathogen, e.g. the skin, lungs and intestine. To target the generation of these cells, for example via vaccination approached, it is important to understand how Trm cells develop. Treg cells are often considered unwanted during vaccination approached, since they are able to reduce immune response.”
“Somewhat surprising, our work shows that they are an important positive factor to consider if Trm cell development should be encouraged. The same may hold true for tumour therapy. The presence of Trm is a positive prognostic factor. If we can harness our knowledge to generate Trm cells that have the properties to reach deep into tumour tissue, this could be very beneficial for future therapy,” stated Dr. Veldhoen.
Moving forwards, the scientists plan to continue studying the behavior of TRM T cells, with a focus on interpreting the mechanisms that regulate the balance of beneficial protective immunity and damaging autoimmunity.
“We always try and follow up on our data, depending on funding obtained. But we have also other project running in the lab. We remain very interested how specialised T cells embedded in tissues behave. How they have adjusted to survive and get appropriately or inappropriately activated. The later can result in tissue-specific damage, such as seen in autoimmune diseases. Understanding how these cells can protect us and how they can negatively affect our health are a main focus of our projects.”
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Dr. Veldhoen’s take-home message: “As so often, our original idea was incorrect. This happens all the time in science and is part of the experience, but can be really tough. Our original hypothesis is not even in the paper. Papers are written when several hypotheses have been discarded and the remaining one has sufficient support and is correctly predicting the outcome of experiments. However, this is portrayed in a paper as “we had a great idea”, “this is what we did” and “it worked”. This often hides enormous amounts of work and disappointment by the authors discarding much work.”
“It is very important for the readers, from lay members of the public to students and postdoctoral fellows, that an a paper is only part of the story. Also in this case, it was a combination of perseverance, good and smart experimentation, knowledge of literature and methodology, disappointment and a lot of hard work and some luck that made the story as it was published.”