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New treatment hope after T cell activation discovery

Friday May 27th 2022

Links between more than 100 genes and immune-system related diseases have been identified for the first time, offering hope of new therapies, British scientists say.

A team from Open Targets, the Wellcome Sanger Institute, Cambridge, UK, and GSK say their first-of-its-kind experiment provides new insights into the sequence and timing of gene activity during the activation of T cells.

The three-year research study shows that numerous disease-linked variants are active during different stages of T cell activation.

Researchers said the findings would help in development of treatments for diseases such as rheumatoid arthritis, type 1 diabetes and Crohn’s disease.

They profiled more than 650,000 individual cells using single-cell RNA sequencing technology to map the timing of gene activity for each cell subtype in the T cell activation process, identifying genes regulated by variations in DNA that were switched on or off in each cell.

More than 6,400 genes involved in the activation process were identified and by comparing their data with known genetic variants for 13 immune diseases, found 127 genes associated with those diseases.

Some of these manifested at specific time points and have not been previously studied, they write in today’s *Nature Genetics*.

First author Dr Blagoje Soskic, of the Wellcome Sanger Institute, said: “By profiling multiple time points during T cell activation, our study emphasises that genetic regulation can be specific for a particular cell state.

“Crucially, we were able to associate DNA variants with changes in the activity of specific genes, in particular cell types, at various times in the activation process. This unprecedented granularity is key to better understanding T cell activation, providing more in-depth data with which to pursue new treatments for immune disorders.”

The research team say their work is the first step to a deeper understanding of immune processes and how they go awry in diseases.

Follow-up studies, in which each gene will be altered individually to observe how this affects the T cell activation, are now needed to provide insights into how immune processes can be affected by variations in DNA, and how immune-mediated diseases develop.

John Lepore, senior vice-president and head of research at GSK, said: “This study is already informing our early discovery portfolio by providing a novel, rich data set we are actively using to select genetically-informed drug targets for further validation experiments.”

The study focused on genes involved in 13 immune diseases, but the approach and data generated can be applied to identifying genes involved in other disorders and the team hope it will shed light on how diseases are related or underpinned by similar biological processes and highlight genetic risk factors.

Dr Gosia Trynka, the senior author of the study from the Wellcome Sanger Institute and Experimental Science Director of Open Targets, said: “Our data will provide crucial insight into key immune system mechanisms, helping us to understand which genes are affected, what might be causing disease, and what factors might be putting patients at risk.

“In particular, the ability to link genetic variants strongly tied to immune diseases with changes in the activity of genes during this activation is a crucial first step to developing new treatments.”

Soskic B, Cano-Gamez E et al. Immune disease risk variants regulate gene expression dynamics during CD4+ T cell activation. *Nature Genetics* 26 May 2022

[abstract]

Tags: Diabetes | Genetics | Rheumatology | UK News

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