Regulatory T cell adaptation in the intestine and skin

The intestine and skin are distinct microenvironments with unique physiological functions and are continually exposed to diverse environmental challenges. Host adaptation at these sites is an active process that involves interaction between immune cells and tissue cells. Regulatory T cells (Treg cells) play a pivotal role in enforcing homeostasis at barrier surfaces, illustrated by the development of intestinal and skin inflammation in diseases caused by primary deficiency in Treg cells. Treg cells at barrier sites are phenotypically distinct from their lymphoid-organ counterparts, and these ‘tissue’ signatures often reflect their tissue-adapted function. We discuss current understanding of Treg cell adaptation in the intestine and skin, including unique phenotypes, functions and metabolic demands, and how increased knowledge of Treg cells at barrier sites might guide precision medicine therapies. The skin and intestine are unique environments at the front line of the immune system. Powrie and colleagues review the distinctive adaptations acquired by regulatory T cells at these barrier surfaces.