Regulatory T cell
The regulatory T cells known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, prevent autoimmune disease. Tregs are immunosuppressive and suppress or downregulate induction and proliferation of effector T cells. Tregs express the biomarkers CD4, FOXP3, CD25 and are thought to be derived from the same lineage as naïve CD4 cells; because effector T cells express CD4 and CD25, Tregs are difficult to discern from effector CD4+, making them difficult to study. Recent research has found that the cytokine TGFβ is essential for Tregs to differentiate from naïve CD4+ cells and is important in maintaining Treg homeostasis. Mouse models have suggested that modulation of Tregs can treat autoimmune disease and cancer and can facilitate organ transplantation and wound healing, their implications for cancer are complicated. Tregs tend to be upregulated in individuals with cancer, they seem to be recruited to the site of many tumors. Studies in both humans and animal models have implicated that high numbers of Tregs in the tumor microenvironment is indicative of a poor prognosis, Tregs are thought to suppress tumor immunity, thus hindering the body's innate ability to control the growth of cancerous cells.
Recent immunotherapy research is studying how regulation of T cells could be utilized in the treatment of cancer. 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, FOXP3; these "Tregs" are different from helper T cells. Another regulatory T cell subset is Treg17 cells. Regulatory T cells are involved in shutting down immune responses after they have eliminated invading organisms, 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, Th3, CD8+CD28-, 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 shown evidence for Foxp3 expression in CD4+CD25- T cells. In humans, Foxp3 is expressed by activated conventional T-cells and thus does not identify human Tregs. 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 Tregs occurs on radio-resistant hematopoietically-derived MHC class II-expressing cells in the medulla or Hassal’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, become Treg cells, although they may not begin to express Foxp3 until the single-positive stage, at which point they are functional Tregs.
Tregs do not have the limited TCR expression of γδ T cells. The process of Treg selection is determined by the affinity of interaction with the self-peptide MHC complex. Selection to become a Treg is a “Goldilocks” process. If a T cell receives an intermediate signal 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 Teff and Treg – the relative proportions determined by the affinities of the T cell for the self-peptide-MHC. In mouse models with TCR-transgenic cells selected on specific-antigen-secreting stroma, deletion or conversion is not complete. Foxp3+ Treg generation in the thymus is delayed by several days compared to Teff cells and does not reach adult levels in either the thymus or periphery until around three weeks post-partum. Treg cells require CD28 co-stimulation and B7.2 expression is 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 Treg functionality, in the thymus, as thymic Tregs from TGF-β insensitive TGFβRII-DN mice are functional; the immune system must be able to discriminate between non-self. When self/non-self discrimination fails, the immune system destroys cells and tissues of the body and as a result causes autoimmune diseases. Regulatory T cells suppress activation of the immune system and prevent pathological self-reactivity, i.e. autoimmune disease. The critical role regulatory T cells play within the immune system is evidenced by the severe autoimmune syndrome that results from a genetic deficiency in regulatory T cells; the molecular mechanism by which regulatory T cells exert their suppressor/regulatory activity has not been definitively characterized and is the subject of intense r
Dendritic cells are antigen-presenting cells of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system, they act as messengers between the adaptive immune systems. Dendritic cells are present in those tissues that are in contact with the external environment, such as the skin and the inner lining of the nose, lungs and intestines, they can be found in an immature state in the blood. Once activated, they migrate to the lymph nodes where they interact with T cells and B cells to initiate and shape the adaptive immune response. At certain development stages they grow branched projections, the dendrites that give the cell its name. While similar in appearance, these are structures distinct from the dendrites of neurons. Immature dendritic cells are called veiled cells, as they possess large cytoplasmic'veils' rather than dendrites. Dendritic cells were first described by Paul Langerhans in the late nineteenth century.
The term dendritic cells was coined in 1973 by Zanvil A. Cohn. For discovering the central role of dendritic cells in the adaptive immune response, Steinman was awarded the Albert Lasker Award for Basic Medical Research in 2007 and the Nobel Prize in Physiology or Medicine in 2011; the morphology of dendritic cells results in a large surface-to-volume ratio. That is, the dendritic cell has a large surface area compared to the overall cell volume; the most common division of dendritic cells is "myeloid" vs. "plasmacytoid dendritic cell": The markers BDCA-2, BDCA-3, BDCA-4 can be used to discriminate among the types. Lymphoid and myeloid DCs evolve from lymphoid and myeloid precursors and thus are of hematopoietic origin. By contrast, follicular dendritic cells are of mesenchymal rather than hematopoietic origin and do not express MHC class II, but are so named because they are located in lymphoid follicles and have long "dendritic" processes; the blood DCs are identified and enumerated in flow cytometry.
Three types of DCs have been defined in human blood: the CD1c+ myeloid DCs, the CD141+ myeloid DCs and the CD303+ plasmacytoid DCs. This represents the nomenclature proposed by the nomenclature committee of the International Union of Immunological Societies. Dendritic cells that circulate in blood do not have all the typical features of their counterparts in tissue, i.e. they are less mature and have no dendrites. Still, they can perform complex functions including chemokine-production, cross-presentation, IFNalpha production. In some respects, dendritic cells cultured in vitro do not show the same behaviour or capability as dendritic cells isolated ex vivo. Nonetheless, they are used for research as they are still much more available than genuine DCs. Mo-DC or MDDC refers to cells matured from monocytes. HP-DC refers to cells derived from hematopoietic progenitor cells. Dendritic cells are derived from hematopoietic bone marrow progenitor cells; these progenitor cells transform into immature dendritic cells.
These cells are characterized by low T-cell activation potential. Immature dendritic cells sample the surrounding environment for pathogens such as viruses and bacteria; this is done through pattern recognition receptors such as the toll-like receptors. TLRs recognize. Immature dendritic cells may phagocytose small quantities of membrane from live own cells, in a process called nibbling. Once they have come into contact with a presentable antigen, they become activated into mature dendritic cells and begin to migrate to the lymph node. Immature dendritic cells phagocytose pathogens and degrade their proteins into small pieces and upon maturation present those fragments at their cell surface using MHC molecules, they upregulate cell-surface receptors that act as co-receptors in T-cell activation such as CD80, CD86, CD40 enhancing their ability to activate T-cells. They upregulate CCR7, a chemotactic receptor that induces the dendritic cell to travel through the blood stream to the spleen or through the lymphatic system to a lymph node.
Here they act as antigen-presenting cells: they activate helper T-cells and killer T-cells as well as B-cells by presenting them with antigens derived from the pathogen, alongside non-antigen specific costimulatory signals. Dendritic cells can induce T-cell tolerance. Certain C-type lectin receptors on the surface of dendritic cells, some functioning as PRRs, help instruct dendritic cells as to when it is appropriate to induce immune tolerance rather than lymphocyte activation; every helper T-cell is specific to one particular antigen. Only professional antigen-presenting cells are able to activate a resting helper T-cell when the matching antigen is presented. However, in non-lymphoid organs, macrophages and B cells can only activate memory T cells whereas dendritic cells can activate both memory and naive T cells, are the most potent of all the antigen-presenting cells. In the lymph node and secondary lymphoid organs, all three cell types can activate naive T cells. Whereas mature dendritic cells are able to activate antigen-specific naive CD8+ T cells, the formation of CD8+ memory T cells requires the interaction of dendritic cells with CD4+ helper T cells.
This help from CD4+ T cells addi
Indoleamine-pyrrole 2,3-dioxygenase is a heme-containing enzyme that in humans is encoded by the IDO1 gene. It is one of three enzymes that catalyze the first and rate-limiting step in the kynurenine pathway, the O2-dependent oxidation of L-tryptophan to N-formylkynurenine, the others being IDO2 and tryptophan 2,3-dioxygenase. IDO has been implicated in immune modulation through its ability to limit T-cell function and engage mechanisms of immune tolerance. Emerging evidence suggests that IDO becomes activated during tumor development, helping malignant cells escape eradication by the immune system. There are crystal structures for human IDO in complex with the inhibitor 4-phenylimidazole and other inhibitors. Indoleamine 2,3-dioxygenase is the first and rate-limiting enzyme of tryptophan catabolism through the kynurenine pathway, thus causing depletion of tryptophan, which can slow the growth of microbes as well as T cells. PGE2 is able to elevate the expression of indoleamine 2,3-dioxygenase in CD11C+ dendritic cells and promotes the development of functional T-regulatory cells, which inhibit T-cell activity.
IDO is an immune checkpoint molecule in the sense that it is an immunomodulatory enzyme produced by some alternatively activated macrophages and other immunoregulatory cells. IDO is known to suppress T and NK cells and activate Tregs and myeloid-derived suppressor cells, promote the growth of new blood cells to feed the tumor. IDO permits tumor cells to escape the immune system by depletion of L-tryptophan in the tumor microenvironment and by production of the catabolic product kynurenine, which selectively impairs the growth and survival of T-cells. A wide range of human cancers such as prostatic, pancreatic, gastric, head, etc. overexpress human IDO. It was thought that the mechanism of tryptophan oxidation occurred by base-catalysed abstraction, but it is now thought that the mechanism involves formation of a transient ferryl species. Interferon-gamma has an antiproliferative effect on many tumor cells and inhibits intracellular pathogens such as Toxoplasma and Chlamydia, at least because of the induction of indoleamine 2,3-dioxygenase.
In tumor cells, IDO expression is controlled by the tumor suppressor Bin1, disabled during cancer development. In mice, IDO has a normal immune checkpoint function in immune tolerance in pregnancy, suppressing the mother's immune system. By 2018 the function of IDO as a checkpoint used by tumors to escape immune surveillance was a focus of research and drug discovery efforts, as well as efforts to understand if it could be used as a biomarker for prognosis; as of 2018, it appeared that overexpression of IDO in some tumors, such as ovarian and endometrial, esophageal cancer, correlated with swifter death, while in kidney and liver cancers it appeared to correlate with better outcomes. A 2018 meta-analysis found that it correlated with worse outcomes in all cancers, but the results were weak. COX-2 inhibitors down-regulate indoleamine 2,3-dioxygenase, leading to a reduction in kynurenine levels as well as reducing proinflammatory cytokine activity. 1-Methyltryptophan is a racemic compound that weakly inhibits indoleamine dioxygenase, but is a slow substrate.
The specific racemer 1-methyl-D-tryptophan is in clinical trials for various cancers. Epacadostat and navoximod are potent inhibitors of the indoleamine 2,3-dioxygenase enzyme and are in clinical trials for various cancers. BMS-986205 is in clinical trials for cancer. 1-Methyltryptophan Tryptophan 2,3-dioxygenase Indoleamine-Pyrrole+2,3,-Dioxygenase at the US National Library of Medicine Medical Subject Headings