LAUSR

Regulatory T cells (Tregs) are a population of T cells that are specialized for suppressing the activation and expansion of aberrant or overreactive lymphocytes. Tregs comprise 5%–10% of the CD4 T-cell population and are characterized mainly by the transcription factor (and lineage marker) forkhead box protein P3 (FOXP3). Other important markers include high surface expression of CD25 (the IL-2 receptor α-chain) and low expression of CD127 (the IL-7 receptor α-chain). Therefore, phenotypically, Tregs can be defined as CD4CD25CD127 T cells, and this combination of markers can be used to identify them from other cells. The role of Tregs in immune regulation and autoimmune diseases became clear after the discovery of intracellular FOXP3 and certain Treg surface markers (e.g., CD25 or IL-2 receptor α). The importance of FOXP3, in particular, was better understood after it was discovered that mutations in the gene encoding of this transcription factor led to a severe autoimmune polyendrocrine syndrome. Mutations in the gene encoding FOXP3 lead to immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX)—a syndrome in which patients manifest features of autoimmunity such as enteropathy, endocrinopathy, and dermatitis, as well as other noninfectious, autoimmune features such as autoimmune hepatitis. This discovery established the importance of Tregs in immune tolerance and additionally opened the door for the idea of adoptive transfer of Tregs as therapy for various autoimmune diseases. In vivo, Tregs originate either through direct differentiation in the thymus or they develop from conventional CD4 T cells in the periphery. In the thymus, immature CD4 single-positive thymocytes that receive T-cell antigen receptor (TCR) signals and have high affinity for selfpeptides differentiate into FOXP3 Treg cells (thymic Tregs or tTregs, also known as natural Tregs or nTregs). In the periphery, conventional CD4 T cells encounter antigens (mostly nonself antigens such as allergens, food, and the commensal microbiota) in the presence of specific factors such as TGF-β, which leads to development of peripheral Treg cells (pTregs). Despite the difference in origin, tTregs and pTregs are similar in function, and there is currently no protein marker to differentiate them in humans. Tregs suppress immune function through both cellcontact mechanisms and the secretion of inhibitory Received: 6 June 2021 Revised: 21 December 2021 Accepted: 22 December 2021