18 January 2019

Scientists have created the first retroviral CRISPR-Cas9 gene editing library to examine the regulation of mouse T cells, it was announced last week.

Although it is known that T helper type 2 cells (Th2) release specific chemicals to tell the body to kill invaders, it is unclear exactly what signals activate these cells or tell them how to develop and which chemical signals to release.

The Wellcome Sanger Institute led the project to map the most important genes for controlling T helper cells, identifying several new regulatory genes. Scientists believe that understanding what regulates T cell development could help to find new drugs against auto-immune diseases that are caused by an over-active immune system.

Published online in the journal Cell, the work focuses on the complex control mechanism, describing how different genes are involved in both activation and development of T helper cells.

The research team created a new genome-wide CRISPR library of 88,000 guide RNAs that enabled them to switch off each of the 20,000 genes from mouse Th2 cells.

They mimicked an infection in cultured Th2 cells and looked at how switching off each single gene in the genome affected the activation or differentiation. They found many genes involved in the regulation of Th2 development, and identified the transcription factor PPARG as being particularly important.

Dr Johan Henriksson, joint first author from the Wellcome Sanger Institute and the Karolinska Institute, Sweden, said: “This is the first ever unbiased genome-wide analysis of the activation and differentiation of T helper cells, helping us understand which signals are involved in immune system regulation. Our study shows that many different types of genes impact both activation and differentiation of these immune cells, indicating how closely linked those two processes are.”

Dr Xi Chen, joint first author from the Wellcome Sanger Institute, said while previous studies have mostly examined one gene at time, the development of a retroviral CRISPR library has enabled them to knock-out each individual gene in mouse T helper cells for the first time.

“We combined the CRISPR screen with other genomic technologies to gain a systematic overview of these immune cells,” he said.

 “This has not only allowed us to identify genes involved in the regulation of Th2 cells but could also be used to study other mouse immune cells and their regulation.”

Source: Henriksson, J., Xi, C., Gomes, T., Ullah, U., Meyer, K.B., Miragaia, R., Duddy, G., Pramanik, J., Yusa, K., Lahesmaa, R., Teichmann, S.A. (2019) “Genome-wide CRISPR screens in T helper cells reveal pervasive cross-talk between activation and differentiation”, Cell, available from doi:10.1016/j.cell.2018.11.044


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