Decision letter: Genetic and epigenetic variation in the lineage specification of regulatory T cells

Abstract

The immune system protects the body from infection. Key to this protection is the ability to mount an immune response that is sufficient to deal with the threat, but is not so large that the damage it causes to the body exceeds its immediate benefit. Immune cells called regulatory T cells (or Treg cells for short) help to shut down the immune response after a threat has been successfully destroyed. They also prevent the immune system from attacking the body's own cells, a phenomenon known as autoimmunity. All cells in the body carry the same set of genes, but the activity of these genes varies between cell types to enable the cells to perform their different jobs. This is possible because our DNA contains regions called regulatory elements that can control the expression of particular genes. These regions can be activated in specific types of cells, which results in specific chemical modifications to DNA that only affect gene activity in those cells. The DNA sequences of these regulatory elements vary between individuals. This ‘genetic variation’ can lead to differences in the chemical modifications that occur to DNA, which is known as epigenetic variation. This means that Treg cells in one person may work in a different way to those in another individual, which could make some individuals more susceptible to autoimmune diseases than others. However, it was not clear how much genetic and epigenetic variation exists in Treg cells. Here, Arvey et al. examined Treg and other immune cells from human and mouse donors. The experiments show that some of the epigenetic modifications present in many individuals only in Treg cells, which indicates that they may be important for the activity of the Treg cells. Unexpectedly, most of the epigenetic modifications were specific to either mice or humans, but Arvey et al. identified a core set of genes that had been modified only in Treg cells in both species. In the human cells, Arvey et al. also identified genetic differences in regulatory elements that are associated with autoimmune diseases. Arvey et al.'s findings suggest that a small set of regulatory elements are crucial to the role of Treg cells in the immune system. Furthermore, genetic variation in these elements can lead to epigenetic changes in Treg cells that contribute to autoimmune diseases in humans. Further study may lead to the development of new treatments for these diseases.