Regulatory T cell

The regulatory T cells, formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. T_reg cells are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. T_reg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4⁺ cells. Because effector T cells also express CD4 and CD25, T_reg cells are very difficult to effectively discern from effector CD4⁺, making them difficult to study. Research has found that the cytokine transforming growth factor beta is essential for T_reg cells to differentiate from naïve CD4⁺ cells and is important in maintaining T_reg cell homeostasis.
Mouse models have suggested that modulation of T_reg cells can treat autoimmune disease and cancer and can facilitate organ transplantation and wound healing. Their implications for cancer are complicated. T_reg cells tend to be upregulated in individuals with cancer, and they seem to be recruited to the site of many tumors. Studies in both humans and animal models have implicated that high numbers of T_reg cells in the tumor microenvironment is indicative of a poor prognosis, and T_reg cells are thought to suppress tumor immunity, thus hindering the body's innate ability to control the growth of cancerous cells. Immunotherapy research is studying how regulation of T cells could possibly be utilized in the treatment of cancer.
The 2025 Nobel Prize in Physiology or Medicine was awarded jointly to Mary E. Brunkow, Frederick J. Ramsdell, and Shimon Sakaguchi for "their discoveries concerning peripheral immune tolerance", largely due to their work identifying and characterizing T_reg cells.

Populations

T regulatory cells are a component of the immune system that suppress immune responses of other cells. This is an important "self-check" built into the immune system to prevent excessive reactions. Regulatory T cells come in many forms with the most well-understood being those that express CD4, CD25, and FOXP3. These T_reg cells are different from helper T cells. Another regulatory T cell subset is T_reg17 cells. Regulatory T cells are involved in shutting down immune responses after they have successfully eliminated invading organisms, and also in preventing autoimmunity.
CD4⁺ FOXP3⁺ CD25 regulatory T cells have been called "naturally occurring" regulatory T cells to distinguish them from "suppressor" T cell populations that are generated in vitro. Additional regulatory T cell populations include Tr1, T_h3, CD8⁺CD28⁻, and Qa-1 restricted T cells. The contribution of these populations to self-tolerance and immune homeostasis is less well defined. FOXP3 can be used as a good marker for mouse CD4⁺CD25⁺ T cells, although recent studies have also shown evidence for FOXP3 expression in CD4⁺CD25⁻ T cells. In humans, FOXP3 is also expressed by recently activated conventional T cells and thus does not specifically identify human T_regs.

Development

All T cells derive from progenitor cells in the bone marrow, which become committed to their lineage in the thymus. All T cells begin as CD4-CD8-TCR- cells at the DN stage, where an individual cell will rearrange its T cell receptor genes to form a unique, functional molecule, which they, in turn, test against cells in the thymic cortex for a minimal level of interaction with self-MHC. If they receive these signals, they proliferate and express both CD4 and CD8, becoming double-positive cells. The selection of T_regs occurs on radio-resistant hematopoietically derived MHC class II-expressing cells in the medulla or Hassall's corpuscles in the thymus. At the DP stage, they are selected by their interaction with the cells within the thymus, begin the transcription of Foxp3, and become T_reg cells, although they may not begin to express Foxp3 until the single-positive stage, at which point they are functional T_regs. T_regs do not have the limited TCR expression of NKT or γδ T cells; T_regs have a larger TCR diversity than effector T cells, biased towards self-peptides.
The process of T_reg selection is determined by the affinity of interaction with the self-peptide MHC complex. Selection to become a T_reg is a "Goldilocks" process - i.e. not too high, not too low, but just right; a T cell that receives very strong signals will undergo apoptotic death; a cell that receives a weak signal will survive and be selected to become an effector cell. If a T cell receives an intermediate signal, then it will become a regulatory cell. Due to the stochastic nature of the process of T cell activation, all T cell populations with a given TCR will end up with a mixture of T_eff and T_reg – the relative proportions determined by the affinities of the T cell for the self-peptide-MHC. Even in mouse models with TCR-transgenic cells selected on specific-antigen-secreting stroma, deletion or conversion is not complete.
After interaction with the self-peptide MHC complex, a T cell must upregulate IL-2R, CD25 and the TNFR superfamily members GITR, OX40 and TNFR2 to become a CD25⁺FOXP3⁻ T_reg cell progenitor. Expression of the transcription factor FOXP3 is then required for this cell to become a mature T_reg. Foxp3 expression is driven by γ-chain dependent cytokines, in particular IL-2 and/or IL-15. IL-2 alone is not sufficient to stimulate Foxp3 expression. While IL-2 is produced by self-reactive thymocytes, IL-15 is produced by stromal cells of the thymus, mainly mTECs and cTECs.
Recently, another subset of T_reg precursors was identified. This subset lacks CD25 and has low expression of Foxp3. Its development is mainly dependent on IL-15. This subset has a lower affinity for self antigens than the CD25⁺Foxp3^high subset. Both subsets generate mature T_reg cells after stimulation with IL-2 with comparable efficiency both in vitro and in vivo. CD25⁺Foxp3^high progenitors exhibit increased apoptosis and develop into mature T_reg cells with faster kinetics than Foxp3^low progenitors. T_regs derived from CD25⁺Foxp3^high progenitors protect from experimental auto-immune encephalomyelitis, whereas those derived from CD25⁺Foxp3^low progenitors protect from T-cell induced colitis.
Mature CD25+Foxp3+ Tregs can be also divided into two different subsets based on the expression level of CD25, GITR, and PD-1. Tregs expressing low amounts of CD25, GITR and PD-1 limit the development of colitis by promoting the conversion of conventional CD4⁺ T cells into pTreg. Tregs highly expressing CD25, GITR and PD-1 are more self-reactive and control lymphoproliferation in peripheral lymph nodes - they may have the ability to protect against autoimmune disorders.
Foxp3⁺ T_reg generation in the thymus is delayed by several days compared to T_eff cells and does not reach adult levels in either the thymus or periphery until around three weeks post-partum. T_reg cells require CD28 co-stimulation and B7.2 expression is largely restricted to the medulla, the development of which seems to parallel the development of Foxp3⁺ cells. It has been suggested that the two are linked, but no definitive link between the processes has yet been shown. TGF-β is not required for T_reg functionality, in the thymus, as thymic T_regs from TGF-β insensitive TGFβRII-DN mice are functional.

Thymic recirculation

It has been observed that some FOXP3⁺ T_reg cells recirculate to thymus. These T_regs were mainly present in thymic medulla, which is the main site of T_reg cells differentiation.
The presence of these cells in the thymus or their addition to fetal thymic tissue culture suppress the development of new T_reg cells by 34–60% without affecting conventional T cells. This suggests that these T_regs only inhibit de novo development of T_reg cells.
The molecular mechanism of this process depends upon the ability of T_regs to adsorb IL-2 from their microenvironments, an ability that allows them to induce the apoptosis of T cells that need IL-2 as main growth factor. Recirculating Tregs in the thymus express high levels of the high-affinity IL-2 receptor α chain, encoded by the Il2ra gene, which gathers IL-2 from thymic medulla and decreases its concentration. In contrast, newly-generated FOXP3⁺ T_reg cells in thymus do not have a high level of Il2ra expression. IL-2 is a cytokine necessary for the development of T_reg cells in the thymus. It is involved in the proliferation and survival of all T cells, but IL-15 may replace its activity in many contexts. However, T_reg cells' development is dependent on IL-2. A population of CD31 negative T_reg cells has been found in the human thymus, suggesting that CD31 may be used as a marker for newly-generated T_reg cells and other T lymphocytes. Mature and peripheral T_reg cells downregulate the expression of CD31, suggesting that this mechanism of thymic T_reg development may also be functional in humans.
There is probably also positive regulation of thymic T_reg cells development caused by recirculating T_reg cells into thymus. A thymic population of CD24 low FOXP3⁺ has been discovered with increased expression of IL-1R2 compared to peripheral T_reg cells. High concentrations of IL-1β caused by inflammation decrease de novo development of T_reg cells in the thymus. The presence of recirculating T_reg cells in the thymus with high IL1R2 expression during inflammatory conditions helps to uptake IL-1β and reduce its concentration in the medulla microenvironment, thus aiding the development of de novo T_reg cells. Binding of IL-1β to IL1R2 on the surface of T_reg cells does not cause signal transduction because the Intracellular Toll interleukin-1 receptor domain, which is normally present in innate immune cells, is absent in T_regs.