. Scientific Frontline: Keeping T cells in check and on target

Thursday, October 26, 2023

Keeping T cells in check and on target

L-R: Professor Stephen Turner & Dr Brendan Russ
Photo Credit: Courtesy of Monash University

Our immune system’s T cells kill tumors and virus-infected cells to prevent disease from spreading to healthy tissues. However, in order to recognize their target and perform their protective function, T cells must undergo a process of maturation which includes being exposed to, then remembering, the unwanted pathogen.

Monash Biomedicine Discovery Institute (BDI) researchers have generated a detailed genetic blueprint that outlines the wiring configuration needed to enhance T cell function, published in Cell Reports.

First author Dr Brendan Russ said that there is great interest in understanding how the maturation of one particular type of T cell, CD8+, is regulated, not only because the body uses CD8+ T cells to fight viral infection and cancer, but also because inappropriate maturation of T cells can result in killing of healthy tissues.

“These maturation processes underlie the ability of T cells to respond to viruses and tumors. What we want is a sweet spot for these T cells such that they become activated only when the body is actually under threat. Indeed, many cutting-edge cancer therapeutics aim to manipulate T cell maturation. So, our findings add to this body of research, and suggest a means of modulating T cell maturation to improve such therapies,” Dr Russ said.

Professor Stephen Turner, senior author on the paper, said, “In the paper we describe how the maturation process of T cells involves bending and looping of the genome, rewiring the cells to acquire and maintain their protective function.

“Importantly, we also identified two molecular switches which are key regulators of this process to keep or return T cells to their resting, non-aggressive state,” Professor Turner said.

“T cells are like wound up springs, they’re ready to become effectors and do their job of attacking viruses and tumors. They have brakes on to keep them inactive. We have been figuring out the mechanisms of taking off the brakes just enough for them to keep the immune system ticking over in a healthy way. The two molecular switches that we have found let us apply the brakes.

“Also, we generated a detailed blueprint that enables the T cell’s genetic architecture to be remodeled in order to help it do its job, identifying how this remodeling can occur and the molecules that are involved. This new information can be used as a resource by others for their research and potentially allow new therapeutic strategies to be developed.”

Dr Russ said, “Next, we aim to use genetic studies to manipulate the mechanism that we’ve described to determine whether T cell responses to infection and cancer can be improved.”

Funding: The work was funded by the National Health and Medical Research Council of Australia; the Australian Research Council; a joint Monash University-University of California, San Diego Seed Development grant (S.J.T. and A.W.G.); and funding from the National Institute of Health, USA.

Published in journalCell Reports

Source/CreditMonash University

Reference Number: bio102623_03

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