Key genes could regulate T cells to treat autoimmune diseases and cancer

Key genes could regulate T cells to treat autoimmune diseases and cancer
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Researchers have discovered a way to control regulatory T cells that help the human body’s immune response.

The researchers at Salk, led by Ye Zheng, have found a way to control the regulatory T cells which act as a cease-fire signal, telling the immune system when it is no longer needed to do its job. The results of the study suggest that controlling the strength of regulatory T cells has potential for treating both cancer and autoimmune diseases.

Regulatory T cells are responsible for stopping the activity of other cells in the immune system when needed and prevent it from attacking the body’s healthy tissue. Underactive regulatory T cells are associated with autoimmune diseases where the immune system attacks the body, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and lupus. Some cancers have higher-than-usual regulatory T cell activity, preventing the immune system from attacking a tumour and allowing its growth.

The study has been published in the journal Immunity.

Modulating T cells

Researchers know that a gene called Foxp3 is a key for the development and function of regulatory T cells, and without it, the body does not form regulatory T cells. The researchers wanted to find other genes that impacted levels of Foxp3 and did so by using CRISPR gene-editing technology to test which genes throughout the genome affected Foxp3. This revealed hundreds of genes, including a handful that encoded different subunits of the SWI/SNF complex, a group of proteins that play a role in turning many other genes on and off by physically.

Ye Zheng, an associate professor in Salk’s NOMIS Center for Immunobiology and Microbial Pathogenesis, said: “Our ultimate goal is to be able to use these genes that modulate regulatory T cells to interfere with autoimmune diseases and cancers.”.

The researchers used CRISPR to selectively remove the SWI/SNF complex genes from regulatory T cells, finding that the deletion of one gene in the ncBAF complex, called Brd9, had a particularly strong effect on the immune cells; regulatory T cells without Brd9 had lower levels of Foxp3 and weakened function.

Eric Chin-San Loo, a graduate student and co-first author of the new paper, said: “Until now, it’s been very hard to fine-tune regulatory T cell activity in the body. This complex allows us to do just that – turn up or down the activity of the immune cells but not enough to cause other forms of disease.”

Animal models

In mouse models with cancer, treatment with the weakened immune cells without Brd9 enabled other immune cells which are normally blocked by the regulatory T cells to infiltrate the tumours and shrink them. In mice with inflammatory bowel disease, however, the weakened regulatory T cells left the immune system attacking the digestive tract unchecked.

Assistant Professor Diana Hargreaves, holder of the Richard Heyman and Anne Daigle Endowed Developmental Chair and the co-corresponding author of the new paper with Zheng, says that future studies could look at whether small molecules can control the activity of the ncBAF complex, which would be more relevant for human therapeutics than genetic methods of altering the proteins, and that such molecules might one day be able to turn down the activity of regulatory T cells to treat cancer, or turn up their activity to treat autoimmune disease.

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