Figure 1.

Types and functions of regulatory T cells (Treg). (a) There are two main types of Treg in humans and mice. Natural Treg (nTreg) are generated in the thymus from precursor T cells recognizing self-antigens presented by thymic antigen presenting cells (APC) via major histocompatibility complex (MHC) II molecules. The differentiation to the Treg phenotype is further influenced by local cytokines. nTreg express high levels of Helios and neuropilin-1 (Nrp1). Treg can also be generated de novo from naïve conventional cluster of differentiation (CD)4⁺ T cells in extrathymic tissues in the presence of interleukin (IL)-2, transforming growth factor (TGF)-β, and retinoic acid following T cell receptor (TCR) engagement. These induced Treg (iTreg) express low levels of Helios and Nrp1. Both Treg types are characterized by the expression of the transcription factor forkhead box protein P3 (Foxp3) and CD25. (b) Treg exert their suppressive function by various cell contact-dependent and -independent mechanisms. These include cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)-dependant suppression of B7-mediated co-stimulation of conventional T cells (Tconv), Lymphocyte activation gene 3 (LAG-3)-mediated suppression of dendritic cell (DC) maturation, IL-2 deprivation of other T cells through expression of high-affinity IL-2 receptors (IL2R), and generation of the immunosuppressive nucleotide adenosine by the ectoenzymes CD39 and CD73. Moreover, Treg secrete the anti-inflammatory cytokines IL-10, TGF-β, and IL-35, and induce apoptosis of inflammatory cells through granzyme/perforin secretion. Treg also shift macrophage polarization from M1 to the M2 type and induce the activity of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) in DCs.