FACTOID # 16: In the 2000 Presidential Election, Texas gave Ralph Nader the 3rd highest popular vote count of any US state.
 
 Home   Encyclopedia   Statistics   States A-Z   Flags   Maps   FAQ   About 
   
 
WHAT'S NEW
 

SEARCH ALL

FACTS & STATISTICS    Advanced view

Search encyclopedia, statistics and forums:

 

 

(* = Graphable)

 

 


Encyclopedia > Regulatory T cell

Regulatory T cells (also known as suppressor T cells) are a specialized subpopulation of T cells that act to suppress activation of the immune system and thereby maintain immune system homeostasis and tolerance to self. The existence of a dedicated population of "suppressor" T cells was the subject of significant controversy among immunologists for many years. However, recent advances in the molecular characterization of this cell population have firmly established their existence and their critical role in the vertebrate immune system. Interest in regulatory T cells has been heightened by evidence from experimental mouse models demonstrating that the immunosuppressive potential of these cells can be harnessed therapeutically to treat autoimmune diseases and facilitate transplantation tolerance or specifically eliminated to potentiate cancer immunotherapy. T cells are a subset of lymphocytes that play a large role in the immune response. ... A scanning electron microscope image of a single neutrophil (yellow), engulfing anthrax bacteria (orange). ... Immunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. ... Classes and Clades See below Male and female Superb Fairy-wren Vertebrates are members of the subphylum Vertebrata (within the phylum Chordata), specifically, those chordates with backbones or spinal columns. ... A scanning electron microscope image of a single neutrophil (yellow), engulfing anthrax bacteria (orange). ... Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. ... Cancer Immunotherapy is the use of monoclonal antibodies (-mab) to specifically target cells. ...

Contents

Definition of T-suppressor cells

T-suppressor 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 so that responses do not go haywire. Suppressot T cells come in many flavors, including those that express the CD8 transmembrane glycoprotein (CD8+ T cells), those that express CD4 and CD25 (CD4+CD25+ regulatory T cells or "Tregs") and other T cell types that have suppressor function. These cells are involved in closing down immune responses after they have successfully tackled invading organisms and also in keeping in check immune responses that may potentially attack one's own tissues ("autoimmunity").


Development

The first evidence that the thymus is critical in the production of Treg cells were the initial experiments by Sakaguchi et al. Neonatal thymectomy at three days of age in mice results in autoimmunity, which provided the data which reignited interest in suppressor/regulatory T cells. All T cells come from progenitor cells from the bone marrow which become committed to their linage in the thymus. All T cells begin as CD4-CD8-TCR- cells at the DN (double-negative) stage, where an individual cell will combine its T cell receptor genes to form a 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 haemopoetically-derived MHC class II expressing cells in the medulla or Hassal’s corpuscles in the thymus. It seems that at the DP (double-positive) stage they are selected by their interaction with the cells within the thymus begin the transcription of Foxp3 and become Treg cells, although they may not begin to express Foxp3 until the single-positive stage, at which point they are functional Tregs. Treg do not have the limited TCR expression of NKT or γδ T cells; Treg have a larger TCR diversity than effector T cells, biased towards self-peptides. Thymus, see Thyme. ... A human infant The word Infant derives from the Latin in-fans, meaning unable to speak. ... A thymectomy is an operation to remove the thymus gland. ... Grays Anatomy illustration of cells in bone marrow. ... Thymus, see Thyme. ... CD4 (cluster of differentiation 4) is a molecule that is expressed on the surface of T helper cells (as well as regulatory T cells and dendritic cells). ... CD8 (cluster of differentiation 8) is a molecule that is expressed on the surface of cytotoxic T cells. ... The T cell receptor or TCR is responsible for recognizing antigen bound to Major histocompatibility complex (MHC). ... MHC may be: an abbreviation for Mount Holyoke College an abbreviation for Mars Hill College an abbreviation for Managed health care an abbreviation for major histocompatibility complex the US Navy hull classification symbol for Coastal Minehunter the Mile High Club This page concerning a three-letter acronym or abbreviation is... TCR can mean: Toronto Civic Railways Total Control Racing, a slotless track mini-car racing that lets you control your car Tottenham Court Road, a street in London which Tottenham Court Road tube station is named after TCR (music), the musical project of Robin Moulder and TC of Satiate. ... The T cell receptor or TCR is responsible for recognizing antigen bound to Major histocompatibility complex (MHC). ...


The exact process of Treg selection is still unknown, but appears to be a process determined by the affinity of interaction with the self-peptide MHC complex. Selection to become a Treg is a “Goldilocks” process; T cell which receives very strong signals will undergo apoptotic death; a cell which 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 then 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. Even in mouse models with TCR-transgenic cells selected on specific-antigen secreting stroma, deletion or conversion is not complete. Someones been eating my porridge, and theyve eaten it all up! Goldilocks and the Three Bears is a popular childrens fairy tale. ...


Foxp3+ Treg generation in the thymus is delayed by several days compared to Teff cells and does not reach adult levels either in the thymus or periphery until around three weeks post partum. Treg 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 Treg development in the thymus, as thymic Treg from TGF-β insensitive TGFβRII-DN mice are functional. Structure of human CD28. ... During the activation of T cells, co-stimulation of molecules is often crucial to the development of an effective immune response. ... Transforming Growth Factor beta (TGF beta) is a biological protein. ... Transforming Growth Factor beta (TGF beta) is a biological protein. ...


Function

To function properly, the immune system must discriminate between self and 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 actively 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. A scanning electron microscope image of a single neutrophil (yellow), engulfing anthrax bacteria (orange). ... Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. ...


The molecular mechanism by which regulatory T cells exert their suppressor/regulatory activity has not been definitively characterized and is the subject of intense research. In vitro experiments suggest that suppressive mechanism requires cell-to-cell contact with the cell being suppressed. However, the immunosuppressive cytokines TGF-beta and Interleukin 10 (IL-10), produced by Th3 and Tr1 cells respectively, have also been implicated in regulatory T cell function. Wiktionary has a definition of: In vitro In vitro (Latin: within glass) means within a test tube, or, more generally, outside a living organism or cell. ... Transforming Growth Factor beta (TGF beta) is a biological protein. ... Interleukin-10 (IL-10 or IL10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine, capable of inhibiting synthesis of pro-inflammatory cytokines like IFN-gamma, IL-2, IL-3, TNFα and GM-CSF by cells such as macrophages and Th1 cells. ...


An important question in the field of immunology is how the immunosuppressive activity of regulatory T cells is modulated during the course of an ongoing immune response. While the immunosuppressive function of regulatory T cells prevents the development of autoimmune disease, it is not desirable during immune responses to infectious microorganisms. Current hypotheses suggest that upon encounter with infectious microorganisms the activity of regulatory T cells may be downregulated, either directly or indirectly, by other cells to facilitate elimination of the infection. Experimental evidence from mouse models suggests that some pathogens may have evolved to manipulate regulatory T cells to immunosuppress the host and so potentiate their own survival. For example, regulatory T cell activity has been reported to increase in several infectious contexts, such as retroviral infections and various parasitic infections including Leishmania and malaria. Genera Alpharetrovirus Betaretrovirus Gammaretrovirus Deltaretrovirus Epsilonretrovirus Lentivirus Spumavirus A retrovirus is a virus which has a genome consisting of two plus sense RNA molecules, which may or not be identical. ... Leishmaniasis is a disease caused by protozoan parasites that belong to the genus Leishmania and is transmitted by the bite of certain species of sand fly, including flies in the genus Lutzomyia in the New World and Phlebotomus in the Old World. ... Malaria is a vector-borne infectious disease that is widespread in tropical and subtropical regions, including parts of the Americas, Asia, and Africa. ...


Molecular characterization

Similar to other T cells, regulatory T cells develop in the thymus. The latest research suggests that regulatory T cells are defined by expression of the forkhead family transcription factor FOXP3 (forkhead box p3). Expression of FOXP3 is required for regulatory T cell development and appears to control a genetic program specifying this cell fate. The large majority of Foxp3-expressing regulatory T cells are found within the major histocompatibility complex (MHC) class II restricted CD4-expressing (CD4+) helper T cell population and express high levels of the interleukin-2 receptor alpha chain (CD25). In addition to the Foxp3-expressing CD4+CD25+, there also appears to be a minor population of MHC class I restricted CD8+ Foxp3-expressing regulatory T cells. Thymus, see Thyme. ... In molecular biology, a transcription factor is a protein that binds DNA at a specific promoter or enhancer region or site, where it regulates transcription. ... Foxp3 is a member of the forkhead/winged-helix family of transcriptional regulators and functions as the master regulator in the development and function of regulatory T cells. ... Foxp3 is a member of the forkhead/winged-helix family of transcriptional regulators and functions as the master regulator in the development and function of regulatory T cells. ... MHC I (1hsa) vs MHC II (1dlh) (more details. ... The introduction to this article provides insufficient context for those unfamiliar with the subject matter. ... A helper (or TH) T cell is a T cell (a type of white blood cell) which has on its surface antigen receptors that can bind to fragments of antigens displayed by the Class II MHC molecules found on professional antigen-presenting cells (APCs). ... Interleukin-2 (IL2) is an interleukin, a type of biological response modifier that can improve the bodys natural response to disease. ...


Prior to the identification of Foxp3, expression of these two cell surface molecules (CD4 and CD25) was used to define the population and thus these cells are often referred to as CD4+CD25+ regulatory T cells (TR or Treg). However, the use of CD25 as a marker for regulatory T cells is problematic as CD25 is also expressed on non-regulatory T cells in settings of immune activation such as during an immune response to a pathogens. As defined by CD4 and CD25 expression, regulatory T cells comprise about 5-10% of the mature CD4+ helper T cell subpopulation in mice and about 1-2% CD4+ helper T cells in humans. Foxp3 is not expressed on activated T cells and the regulatory T cell population as more accurately defined by Foxp3 expression extends beyond the CD4+CD25+ operational definition. Typically, high levels of CTLA-4 (cytotoxic T-lymphocyte associated molecule-4) and GITR (glucocorticoid-induced TNF receptor) are also expressed on regulatory T cells however the functional significance of this expression remains to be defined. There is a great interest in identifying cell surface markers that are uniquely and specifically expressed on all Foxp3-expressing regulatory T cells. However, to date no such molecule has been identified.


CD4+CD25+ regulatory T cells have also been referred to as "naturally-occurring" regulatory T cells to distinguish them from "suppressor" T cell populations that are generated in vitro. In fact, the "naturally-occurring" CD4+CD25+ regulatory T cell population is a subset of the total Foxp3-expressing regulatory T cell population. The regulatory T cell field is further complicated by reports of additional "suppressor" T cell populations, including Tr1, CD8+CD28-, and Qa-1 restricted T cells. However the contribution of these populations to self-tolerance and immune homeostasis is less well defined.


Recent evidence suggests mast cells may be important mediators of Treg-dependent peripheral tolerance.[1]


Genetic deficiency

Genetic mutations in the gene encoding Foxp3 have been identified in both humans and mice based on the heritable disease caused by these mutations. This disease provides the most striking evidence that regulatory T cells play a critical role in maintaining normal immune system function. Humans with mutations in Foxp3 suffer from a severe and rapidly fatal autoimmune disorder known as Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome.[2][3]


The IPEX syndrome is characterized by the development of overwhelming systemic autoimmunity in the first year of life resulting in the commonly observed triad of watery diarrhea, eczematous dermatitis, and endocrinopathy seen most commonly as insulin-dependent diabetes mellitus. Most individuals have other autoimmune phenomena including Coombs positive anemia, autoimmune thrombocytopenia, autoimmune neutropenia, and tubular nephropathy. The majority of affected males die within the first year of life of either metabolic derangements or sepsis. An analogous disease is also observed in a spontaneous Foxp3 mutant mouse known as “scurfy”. For the disease characterized by excretion of large amounts of very dilute urine, see diabetes insipidus. ...


Review Articles from the Scientific Literature

These two comprehensive reviews include valuable historical perspectives on experiments that have led to the current understanding of regulatory T cells.

  • Shevach, Ethan M. (2002). "CD4+CD25+ suppressor T cells: more questions than answers." Nature Reviews Immunology 2, 389-400. PubMed Link Journal Link
  • Sakaguchi, Shimon (2004). "Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses." Annual Review of Immunology 22, 531-562. PubMed Link Journal Link

The following group of review articles were published as part of a special "Focus on Regulatory T cells" issue of the journal Nature Immunology. The issue also includes a "Classics" section listing important primary literature from the field as recommended by a group of prominent immunologists. A subscription (either personal or university) may be required to access this content.

  • Fontenot, Jason D., and Rudensky, Alexander. Y. (2005). "A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3." Nature Immunology 6, 331-337. PubMed Link Journal Link
  • von Boehmer, Harald (2005). "Mechanisms of suppression by suppressor T cells." Nature Immunology 6, 338-344. PubMed Link Journal Link
  • Shimon Sakaguchi (April 2005). "Naturally arising Foxp3-expressing CD4+CD25+ regulatory T cells in immunological tolerance to self and non-self". Nature Immunology 6 (4): 345-352. PMID 15785760. 
  • Yasmine Belkaid, and Barry T. Rouse (April 2005). "Natural regulatory T cells in infectious disease". Nature Immunology 6 (4): 353-360. PMID 15785761. 

See also:

  • Hong Jiang and Leonard Chess (2004). "An integrated view of suppressor T cell subsets in immunoregulation". J. Clin. Invest. 114 (9): 1198–1208.. 

The Journal of Clinical Investigation (JCI or J Clin Invest) is a leading biomedical journal, which is radically different from many of its peers in having a high impact factor (in 2005, 15. ...

References

  1. ^ Lu, et al. "Mast cells are essential intermediaries in regulatory T cell tolerance Nature 2006; 442(7106):997-1002.
  2. ^ Online Mendelian Inheritance in Man IPEX
  3. ^ GeneTests at NIH/UW ipex

The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome. ... The National Institutes of Health (NIH) is the primary agency of the United States government responsible for medical research. ... The University of Washington, founded in 1861, is a public research university in Seattle, Washington. ...

External links

  • MeSH Regulatory+T-Cells

  Results from FactBites:
 
Regulatory T cell - Wikipedia, the free encyclopedia (1224 words)
Regulatory T cells (also known as suppressor T cells) are a specialized subpopulation of T cells that act to suppress activation of the immune system and thereby maintain immune system homeostasis and tolerance to self.
Interest in regulatory T cells has been heightened by evidence from experimental mouse models demonstrating that the immunosuppressive potential of these cells can be harnessed therapeutically to treat autoimmune diseases and facilitate transplantation tolerance or specifically eliminated to potentiate cancer immunotherapy.
regulatory T cell population is a subset of the total Foxp3-expressing regulatory T cell population.
Stem cell - Wikipedia, the free encyclopedia (1724 words)
Embryonic stem cells are cultured cells obtained from the undifferentiated inner mass cells of an early stage human embryo (sometimes called a blastocyst, which is an embryo that is between 50 to 150 cells).
Cancer stem cells arising through malignant transformation of adult stem cells are proposed to be the source of some or all tumors and cause metastasis and relapse of the disease.
Embryonic stem cell research is particularly controversial because, with the present state of technology, starting a stem cell 'line' requires the destruction of a human embryo and/or therapeutic cloning.
  More results at FactBites »

 
 

COMMENTARY     


Share your thoughts, questions and commentary here
Your name
Your comments

Want to know more?
Search encyclopedia, statistics and forums:

 


Press Releases |  Feeds | Contact
The Wikipedia article included on this page is licensed under the GFDL.
Images may be subject to relevant owners' copyright.
All other elements are (c) copyright NationMaster.com 2003-5. All Rights Reserved.
Usage implies agreement with terms, 1022, m