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CRISPR screen unveils the stickiness of T cells

A new study has pinpointed a previously unknown molecular inhibitor of T cell adhesion.

The study, published in Science Signalling, sheds light on the adhesive properties of T cells and how it can influence these cells to migrate into tissues and support the immune system.

Researchers from the National Institute of Allergy and Infectious Diseases used a CRISPR-based screen and discovered an important molecular release factor. This release factor limited the adhesion of T cells to other cells and enabled T cells to migrate throughout the lymphatic system.

Adhesive T cells

T cells can move towards tissues to fight infections, but they must initially pass through the body’s lymph nodes. To navigate the lymphatic system or stimulate antibody production, T cells adhere to other types of cells, such as endothelial cells or B cells.

The process of T cell adhesion is a delicate balance, as too much or too little adhesion can stop T cells from reaching their destinations or releasing from associated cells. The T cell protein LFA-1 is closely implicated in these pathways and promotes cell adhesion, but many of its binding partners have not been characterised.

“Understanding LFA-1 regulation is critical in the context of developing therapeutics that modulate T cell activity,” the authors wrote.

CRISPR screen investigates molecular regulators

The team used CRISPR to screen nearly 600 genes. They investigated the main molecular players that regulate T cell adhesion and targeted proteins that bind to PIP3, a signalling lipid that activates LFA-1.

The study identified multiple proteins that regulated the binding of LFA-1. They revealed that a protein called RASA3 inhibited LFA-1’s activation in mouse T cells, and T cells that lacked RASA3 couldn’t properly enter or exit lymph nodes.

Furthermore, mice with T cells deficient in RASA3 showed weak responses to immunisation, suggesting that the protein acts as a necessary countermeasure for T cell adhesion.

How these pathways contribute to the phenotypes of activated PI3Kδ syndrome and the broader implications for treatment and the use of PI3Kδ inhibitors are intriguing questions for future studies.

The authors noted, “Our data shed further light on the intricate mechanisms controlling T cell migration and the dynamic regulation of lymphocyte homing that is required for proper immunity.”

Image Credit: Canva

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