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30 Apr 2021

Researchers discover regulators of tissue-resident memory T cells

Researchers have discovered two new regulators of the formation and function of tissue-resident memory T (TRM) cells, which if harnessed into therapeutics, carries great potential for the prevention and treatment of a broad spectrum of diseases.

TRM cells can be found in virtually all tissues, including the skin, gut and lung and act as a frontline defence against invading microbes or cancer cells, making them a great target to treat infections and cancer.

Led by University of Melbourne Professor Thomas Gebhardt, laboratory head at the Doherty Institute and Postdoctoral Fellow, Dr Katharina Hochheiser, the researchers looked at TRM cells in the skin, in mouse models of viral infection and autoimmunity.

The two new regulators of the TRM cells that the research team identified in this study are proteins, named Ptpn2 and KLRG1.

“Ptpn2 regulated the activation of T cells during infection – it ensures the cells don’t get too activated which is important to maintain a pool of cells that can still develop into TRM cells, in order to fight persistent or recurring infection,” Dr Hochheiser said.

“Many Ptpn2-deficient T cells that were activated during viral infection expressed KLRG1. KLRG1 is expressed on short-lived effector cells, and isn’t expressed on TRM cells but no one really knew whether the protein itself prevents memory cell formation, until now.”

The team identified that when KLRG1 is experimentally expressed in cells that wouldn’t normally express it, those cells showed a defect in the formation of TRM cells.

“This is a big step in the understanding of how localised T cell memory is facilitated. It highlights that for example in the design of vaccines, strong T cell activation is not necessarily the key but activation of T cells needs to be regulated to ensure the formation of a pool of KLRG1 negative cells that can fight infections in the future,” she explained.

Another aspect of the study which was published today in the Journal of Experimental Medicine, looked specifically at the role of the Ptpn2 protein in skin TRM functionality.

“We found that when TRM cells formed that lacked the Ptpn2 protein, they are much more reactive in the context of viral infection and autoimmunity.  Therapeutic Ptpn2 inhibition may potentially prove beneficial in fighting infections or cancer but could at the same time come with side effects like autoimmune inflammation.”

This research was done in collaboration with Monash University and the Peter MacCallum Cancer Centre.