Regulatory T cell

You don't need to be Editor-In-Chief to add or edit content to WikiDoc. You can begin to add to or edit text on this WikiDoc page by clicking on the edit button at the top of this page. Next enter or edit the information that you would like to appear here. Once you are done editing, scroll down and click the Save page button at the bottom of the page.

WikiDoc Resources for Regulatory T cell
Articles
Most recent articles on Regulatory T cell Most cited articles on Regulatory T cell Review articles on Regulatory T cell Articles on Regulatory T cell in N Eng J Med, Lancet, BMJ
Media
Powerpoint slides on Regulatory T cell Images of Regulatory T cell Photos of Regulatory T cell Podcasts & MP3s on Regulatory T cell Videos on Regulatory T cell
Evidence Based Medicine
Cochrane Collaboration on Regulatory T cell Bandolier on Regulatory T cell TRIP on Regulatory T cell
Clinical Trials
Ongoing Trials on Regulatory T cell at Clinical Trials.gov Trial results on Regulatory T cell Clinical Trials on Regulatory T cell at Google
Guidelines / Policies / Govt
US National Guidelines Clearinghouse on Regulatory T cell NICE Guidance on Regulatory T cell NHS PRODIGY Guidance FDA on Regulatory T cell CDC on Regulatory T cell
Books
Books on Regulatory T cell
News
Regulatory T cell in the news Be alerted to news on Regulatory T cell News trends on Regulatory T cell
Commentary
Blogs on Regulatory T cell
Definitions
Definitions of Regulatory T cell
Patient Resources / Community
Patient resources on Regulatory T cell Discussion groups on Regulatory T cell Patient Handouts on Regulatory T cell Directions to Hospitals Treating Regulatory T cell Risk calculators and risk factors for Regulatory T cell
Healthcare Provider Resources
Symptoms of Regulatory T cell Causes & Risk Factors for Regulatory T cell Diagnostic studies for Regulatory T cell Treatment of Regulatory T cell
Continuing Medical Education (CME)
CME Programs on Regulatory T cell
International
Regulatory T cell en Espanol Regulatory T cell en Francais
Businness
Regulatory T cell in the Marketplace Patents on Regulatory T cell
Experimental / Informatics
List of terms related to Regulatory T cell

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Phone:617-525-6884

Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.

Regulatory T cells (sometimes 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-antigens. The existence of a dedicated population of suppressive 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 regulatory cell 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 so that responses do not go haywire. Regulatory T cells come in many flavors, including those that express the CD8 transmembrane glycoprotein (CD8+ T cells), those that express CD4, CD25 and Foxp3 (CD4+CD25+ regulatory T cells or "Tregs") and other T cell types that have suppressive 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).

CD4⁺Foxp3⁺ regulatory T cells have been referred to as "naturally-occurring" regulatory T cells to distinguish them from "suppressor" T cell populations that are generated in vitro. The regulatory T cell field is further complicated by reports of additional suppressive 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.

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 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.

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.

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.

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.

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 have given mixed results regarding the requirement of cell-to-cell contact with the cell being suppressed. The immunosuppressive cytokines TGF-beta and Interleukin 10 (IL-10) have also been implicated in regulatory T cell function.

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.

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.

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 (T_R or T_reg). 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.

Recent evidence suggests that 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.^[1][1]

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”.

Footnotes

External links

• MeSH Regulatory+T-Cells

v • d • e Blood
General	Plasma – Hematopoietic stem cells
Lymphoid – WBC	T cells: Cytotoxic CD8+, Helper CD4+/Regulatory, γδ, Natural Killer T cell B cells: Plasma, Memory Natural killer cells (Lymphokine-activated killer cell) Null cell
Myeloid – WBC	Monocytes/Macrophages (Histiocytes, Kupffer cells, Langhans giant cells, Microglia, Osteoclasts, Epithelioid cells) Granulocytes (Neutrophil, Eosinophil, Basophil) – Mast cell precursors Dendritic cells (Langerhans cells, Follicular dendritic cells) Megakaryoblast – Megakaryocyte – Platelets
Myeloid – RBC	Reticulocyte – Normoblast

v • d • e Immune system / Immunology
Systems	Adaptive immune system vs. Innate immune system • Humoral immune system vs. Cellular immune system • Complement system (Anaphylatoxins) • Intrinsic immune system
Antibodies and antigens	Antibody (Monoclonal antibodies, Polyclonal antibodies, Autoantibody) • Allotype • Isotype • Idiotype • Antigen (Superantigen)
Immune cells	White blood cells (T cell, B cell, NK cell, Mast cell, Basophil, Eosinophil) • Phagocyte (Neutrophil, Macrophage, Dendritic cell) • Antigen-presenting cell • Reticuloendothelial system
Immunity vs. tolerance	Immunity • Autoimmunity • Allergy • Tolerance (Central) • Immunodeficiency
Immunogenetics	Somatic hypermutation • V(D)J recombination • Immunoglobulin class switching • MHC / HLA
Substances	Cytokines • Opsonin • Cytolysin
Other	Inflammation • Epitope (Hapten) • Cross-reactivity

v • d • e WikiDoc Research Resources for Regulatory T cell (Click show to right to view)
Articles on Regulatory T cell	Most recent articles on Regulatory T cell • Most cited articles on Regulatory T cell • Review articles on Regulatory T cell • Articles on Regulatory T cell in N Eng J Med, Lancet, BMJ
Media (Slides, Video, Images, MP3) on Regulatory T cell	Powerpoint slides on Regulatory T cell • Images of Regulatory T cell • Photos of Regulatory T cell • Podcasts & MP3s on Regulatory T cell • Videos on Regulatory T cell
Evidence Based Medicine Regarding Regulatory T cell	Cochrane Collaboration on Regulatory T cell • Bandolier on Regulatory T cell • TRIP on Regulatory T cell
Cost Effectiveness of Regulatory T cell	Cost Effectiveness of Regulatory T cell
Clinical Trials Involving Regulatory T cell	Ongoing Trials on Regulatory T cell at Clinical Trials.gov • Trial results on Regulatory T cell • Clinical Trials on Regulatory T cell at Google
Guidelines / Policies / Government Resources (FDA/CDC) Regarding Regulatory T cell	US National Guidelines Clearinghouse on Regulatory T cell • NICE Guidance on Regulatory T cell • NHS PRODIGY Guidance • FDA on Regulatory T cell • CDC on Regulatory T cell
Textbook Information on Regulatory T cell	Books and Textbook Information on Regulatory T cell
Pharmacology Resources on Regulatory T cell	Dosing of Regulatory T cell • Drug interactions with Regulatory T cell • Side effects of Regulatory T cell • Allergic reactions to Regulatory T cell • Overdose information on Regulatory T cell • Carcinogenicity information on Regulatory T cell • Regulatory T cell in pregnancy • Pharmacokinetics of Regulatory T cell •
Genetics, Pharmacogenomics, and Proteinomics of Regulatory T cell	Genetics of Regulatory T cell • Pharmacogenomics of Regulatory T cell • Proteomics of Regulatory T cell
Newstories on Regulatory T cell	Regulatory T cell in the news • Be alerted to news on Regulatory T cell • News trends on Regulatory T cell
Commentary on Regulatory T cell	Blogs on Regulatory T cell
Patient Resources on Regulatory T cell	Patient resources on Regulatory T cell • Discussion groups on Regulatory T cell • Patient Handouts on Regulatory T cell • Directions to Hospitals Treating Regulatory T cell • Risk calculators and risk factors for Regulatory T cell
Healthcare Provider Resources on Regulatory T cell	Symptoms of Regulatory T cell • Causes & Risk Factors for Regulatory T cell • Diagnostic studies for Regulatory T cell • Treatment of Regulatory T cell
Continuing Medical Education (CME) Programs on Regulatory T cell	CME Programs on Regulatory T cell
International Resources on Regulatory T cell	Regulatory T cell en Espanol • Regulatory T cell en Francais
Business Resources on Regulatory T cell	Regulatory T cell in the Marketplace • Patents on Regulatory T cell
Informatics Resources on Regulatory T cell	List of terms related to Regulatory T cell

dv:ރެގިއުލޭޓަރީ ޓީ ސެލް

de:Regulatorische T-Zelle fr:Régulateur T he:תא T רגולטורי nl:Suppressor T-cel

WikiDoc Help Menu Quick Start.. Get Started Here! How to Login How to Search Pages How to Start a New Page How to Edit a Page Cheat Sheet Editing basics Learning Basic Formatting How to make Links in WikiDoc & to External Sites How to Make Lists How to Ignoring Formatting Adding References or Footnotes to Articles Tracking Changes You Have Made How to Put an Article Into a Category When Multiple Topics Should Go To The Same Page (MI, Acute MI, AMI) Using Redirection Advanced editing How to Make Tables How to Insert Images and Other Media How to Add Video Help:How to Make Columns Web Colors How To Make Templates How to Move Pages Inserting Dynamic Dates and Times Inserting WikiDoc Statistics Editing the Table of Contents Communicating your edits Let others know what you changed: The importance of Edit Summaries Minor Edits Edit Conflicts Help Videos You Can Watch Getting Started Video

Acknowledgement and Attribution Regarding Sources of Content

Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .