Funding: NHMRC, Howard Hughes Medical Institute and Bill & Melinda Gates FoundationDOI: 10.1038/s41590-022-01273-4
Researchers at the Peter Doherty Institute for Infection and Immunity (Doherty Institute) have identified how to increase the ability of tissue-resident memory (TRM) T cells to help fight viral infections and certain cancers.
This discovery adds to the growing knowledge about the enormous potential of T-cell-based vaccines and immunotherapies.
TRM cells are a type of immune cell found in body tissues that have been shown to be critical for immune protection against viral infections and solid tumors.
These cells are particularly important for the control of pathogens on epithelial surfaces of the body such as the skin and intestines, which are sites of entry for numerous microbes.
However, only some subsets of TRM cells appeared to remain stationary in these epithelial tissues, and until now, it was not understood why.
Published today in Nature Immunology, the research team led by University of Melbourne Professor Laura Mackay, Head of Laboratory at the Doherty Institute, identified the molecular switch that allows TRM cells to reside in the ‘epithelium and showed that this molecule could be deployed to enforce. tissue residence in other cells to provide additional protection against viral infection.
T cells can be divided into two main types, CD8+ and CD4+, explains Dr Raissa Fonseca of the University of Melbourne, an ARC DECRA researcher in the laboratory of Professor Laura Mackay.
“While TRM CD8 + cells have been identified in these epithelial layers, we have never understood why TRM CD4 + cells were not there,” said Dr. Fonseca.
“What was it that allowed CD8 + TRM cells to behave this way and remain in epithelial tissues?”
The team examined the genetic differences between these TRM cell subtypes.
“We found key differences in the genetic drivers of TRM CD8+ and CD4+ cells. Using CRISPR/Cas9 gene editing, we showed that while TRM CD8+ cells depended on the molecular regulator Runx3, cells TRM CD4+ cells used an alternative regulator: Runx1,” explained Dr. Fonseca.
“Runx3 was the key. This was the gene that allowed CD8+ TRM to survive in the epithelium, so we simply genetically altered its expression in CD4+ TRM cells.
“Surprisingly, we found that by manipulating this gene, CD4 + TRM cells could persist in the epithelial layer of the skin and gut, and could protect more effectively against viral infection.”
The co-lead author of the paper, Dr Thomas Burn from the University of Melbourne, explained that improving the formation of TRM cells is highly desirable for infection control.
“TRM cells exist at pathogen entry points, where they are ready to attack immediately when the body is in danger.
“Decoding how TRM cells survive in these frontline tissues greatly helps us understand how these cells can be harnessed to fight infection.”
The team predicts that this discovery could lead to better therapies to treat infections and cancer.
“New treatments for disease can always be traced back to discovery research,” Professor Mackay said.
“Understanding how T cells can be induced in barrier tissues is a crucial step in developing new vaccines and immunotherapies.”