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Most infections enter the body through barrier organs such as the skin, lungs and gut. A group of immune cells termed tissue-resident memory T (TRM) cells permanently live in these organs where they act as rapid first-responders to danger, such as infections and cancer. However, scientists are yet to elucidate how to make more TRM cells in a specific organ and what keeps them there.

Led by the University of Melbourne’s Professor Laura Mackay, a Laboratory Head and Immunology Theme Lead at the Doherty Institute, the research team uncovered how retinoic acid, a molecule made from vitamin A that is commonly found in foods such as oily fish and eggs, alters the location and function of TRM cells. Notably, the researchers found that retinoic acid boosted TRM cells in the gut and helped them stay and survive there, suggesting that it could be used to improve long-term immunity within this tissue.

First author of the study published recently in Immunity and PhD Candidate in the University of Melbourne’s Mackay lab at the Doherty Institute, Andreas Obers, explained how changes in retinoic acid levels affect TRM cell behaviour.

“We found that retinoic acid was like a ‘molecular thermostat’ controlling the location of TRM cells in different organs. In our experiments, we observed that higher levels of retinoic acid would result in more TRM cells in the gut and liver. Conversely, we found that retinoic acid prevented the formation of TRM cells in the skin,” Mr Obers said.

Dr Maximilien Evrard, an Australian Research Council DECRA Research Fellow at the Doherty Institute and co-senior author of the study, highlighted the role of retinoic acid, and vitamin A, in our immune system.

“Interestingly, retinoic acid not only anchors TRM cells within tissues, but also limits their tendency to migrate away, particularly in the intestines. This may partly explain the weakened local immune defences in patients with vitamin A deficiency, a condition often associated with malnutrition in developing countries,” Dr Evrard said.

“This exciting finding means we could ‘fine-tune’ where immune cells need to be in order to combat specific disease,” he added.

Professor Mackay underscored the potential of this research in enhancing immune resilience and managing autoimmune responses.

“Therapeutic strategies that regulate the amount of retinoic acid in the body may offer a new approach to control tissue immunity,” Professor Mackay said.

“For example, boosting retinoic acid may aid in protective immune responses against foodborne infections, while reducing levels of retinoic acid could remove TRM cells contributing to autoimmune disorders such as inflammatory bowel disease.”

• Peer review: Obers A, et al. Retinoic acid and TGF-b orchestrate organ-specific programs of tissue residency. Immunity (2024). DOI:  https://doi.org/10.1016/j.immuni.2024.09.015
• Funding: This study was supported by the NHMRC, Australian Research Council, Howard Hughes Medical Institute, Bill and Melinda Gates Foundation, Cancer Research Institute and Sylvia and Charles Viertel Charitable Foundation.
• Collaboration: This study was led by Professor Laura Mackay, in collaboration with researchers at Monash University, University of Bonn and Stanford University.