Nature and nurture in Foxp3+ regulatory T cell development, stability, and function

Abstract

Foxp3+ regulatory T lymphocytes (Treg) are critical homeostatic regulators of immune and inflammatory responses. Their absence leads to fulminant multi-organ autoimmunity. This review explores recent studies that have altered our emerging view of the development, stability, and plasticity of these cells. Treg appear not to be a single entity, but a family of immunomodulatory cell types with shared capabilities. On a first level, Treg may alternatively form in response to developmental cues in the thymus as a distinct lineage of CD4+ T cells, or adaptively, in response to environmental cues received by mature conventional CD4+ T lymphocytes. These two populations bear distinct specificity, stability, and genetic profiles, and are differentially used in immune responses. Secondarily, in a manner analogous to the generation of Th1, Th2, and other T cell subsets, Treg may further specialize, adapting to the needs of their immunologic surroundings. Treg therefore comprise developmentally distinct, functionally overlapping cell populations that are uniquely designed to preserve immunologic homeostasis. They combine both an impressive degree of stability and adaptability.

Modulation of the Immune and Inflammatory Responses by Plasmodium falciparum Schizont Extracts: Role of Myeloid Dendritic Cells in Effector and Regulatory Functions of CD4 + Lymphocytes

“…Control cultures were also set up with US MDDC. Figure 3C shows the results of the cytofluorometric analysis performed with anti-CD25 and anti-Foxp3 antibodies in 5-day cultures of CD4 cells from 18 different subjects; although a dose-response effect is evident also in these experimental conditions, the saturation of Treg cell expansion is reached with MDDC exposed to 10 g/ml of PfSE, suggesting that MDDC could present high-affinity ligands at low-antigen density, promoting Treg cell generation as reported in different systems (25).…”

“…Dendritic cells could be involved in Treg cell generation either through the presentation of ligands which preferentially expand Treg cell populations or through mechanisms independent of specific TCR activation based on the production of "suppressive" cytokines. In our experimental conditions, the functional phenotype of MDDC acquired in the presence of parasitic extracts resembles that of semimature dendritic cells with prevalent tolerogenic functions (35), and the maximum expansion of Treg cell population induced is achieved by MDDC pulsed with relatively small amounts of PfSE (1 to 10 g/ml, corresponding to 10 4 to 10 5 iRBC), indicating that, under conditions of low antigenic concentrations, MDDC may present high-affinity ligands to T cells which primarily promote Treg induction (25). Preliminary results obtained in our laboratory by using live parasites also show that MDDC activated by iRBC at low iRBC/MDDC ratios (0.1:1, 1:1) are equally effective in inducing Treg cells compared to parasite extracts.…”

An increased population of regulatory T cells improves the pathophysiology of placental ischemia in a rat model of preeclampsia

“…Regulatory T cells play a major role in the development and maintenance of immune tolerance (8) and are classically identified by surface expression of CD4 and CD25, as well as the transcription factor forkhead box protein 3 (FoxP3) (8,35). Regulatory T cells regulate the immune system by suppressing autoreactive T cells, dampening inflammation, and inducing tolerance in normal pregnancy.…”

GITR+ regulatory T cells in the treatment of autoimmune diseases

“…CD4 + Tregs can be subdivided into two distinct populations: thymus-derived Tregs (tTregs) develop in the thymus as a distinct lineage and are characterized by a stable phenotype and function, whereas peripherally derived Tregs (pTregs) appear to be converted extrathymically from conventional CD4 + effector T cells in response to microenvironmental signals. Cells belonging to the pTreg population, which include transforming growth factor (TGF)-β-producing Th3 cells and interleukin (IL)-10-producing Tr1 cells exhibit a high degree of plasticity [2] and appear to be able to expand in response to specific needs [3]. However, some tTregs are memory T cells that are able to expand under various conditions, such as in certain tumors [4].…”