Tregs are a subset of CD4+ T cells that suppress the proliferation and cytokine production of activated T cells whose TCRs have been engaged by peptide–MHC, even in the presence of co-stimulation. Hence, as opposed to anergy, which operates in a cell-intrinsic fashion, Tregs block responsiveness in trans, by modulating responses of other cells. Tregs arise in two ways: “thymic” Tregs (tTregs, also termed natural Tregs, nTregs) that acquire function during develop ment in the thymus (described earlier) and “inducible” Tregs (iTregs) that are generated through the differentiation of naive CD4+ T cells in the periphery. Both tTregs and iTregs are characterized by expression of the key transcription factor FoxP3 and by surface expression of CD25, a subunit of the IL-2 receptor.

As noted, there are multiple steps and checkpoints that occur during development of T cells in the thymus. After reaching the DP stage, T cells test their TCR for reactivity against peptide–MHC complexes presented by thymic APCs and epithelial cells. Cells bearing TCRs with no reactivity undergo apoptosis (failed positive selection) as do cells with very strong TCR reactivity (through negative selection). Only cells whose TCRs have moderate affinity for pep tide–MHC continue to mature. Within this continuum of permitted reactivity, those cells with TCRs exhibiting the highest affinity for peptide–MHC are induced to express FoxP3 and develop into Tregs. In the periphery, these cells respond to TCR stimulation by diminishing the response of “conventional” T effector cells, thus downregulating immune responses.

iTregs act similarly to tTregs, but these cells do not leave the thymus poised to have suppressive function. Instead, these cells arise from naive T cells that encounter antigen in the secondary lymphoid structures. Similar to other CD4+ subsets, iTregs are induced on the basis of prevailing cytokine conditions and which receptor ligand interactions predominate during this initial antigen encounter. Regardless of whether they arise in the thymus or are induced in the periphery, Tregs exert their immunosuppressive functions on a variety of immune cells, including CD4+ and CD8+ T cells, DCs, B cells, macrophages, and NK cells, within their microenvironment. Tregs mediate these immunosuppressive effects through the secretion of suppressor cytokines such as IL-10, IL-35, and TGF-β, the consumption of local concentrations of IL-2, and the induction of apoptosis or cell cycle arrest through direct cell-to-cell contact, likely through direct presentation of TGF- β by cell surface receptors on Tregs (Fig.1).

Fig1. REGULATORY T-CELL ACTIONS. T-regulatory cells (Tregs) act to suppress other T cells through a multitude of mechanisms. Tregs can act in a cell contact–dependent manner by competing directly for stimulatory ligands on the antigen-presenting cell (APC), by absorbing essential growth factors, such as interleukin-2 (IL-2), or by directly transmit ting an as-yet uncharacterized negative signal to either the T cell or the APC. Alternatively, Tregs can use long-range suppressive mechanisms by means of the cytokines IL-10, IL-35, and transforming growth factor-β (TGF-β). (From Rich RR, et al. Clinical Immunology. 5th ed. Elsevier; 2019.)

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