Thymocytes are hematopoietic progenitor cells present in the thymus. The primary function of thymocytes is the generation of T lymphocytes T cells. The thymus provides an inductive environment, which allows for the development and selection of physiologically useful T cells.
The processes of beta-selection, positive selection, and negative selection shape the population of thymocytes Mature double a peripheral pool of T cells that are able to respond to foreign pathogens and are immunologically tolerant towards self antigens. Thymocytes are classified into a Mature double of distinct maturational stages based on Mature double expression of cell surface markers.
The earliest thymocyte stage is the double negative stage negative for both CD4 and CD8which more recently has been better described as Lineage-negative, and which can be divided into four substages.
The next major stage is the double positive stage positive for both CD4 and CD8. The final stage in maturation is the single positive stage positive for either CD4 or CD8. They produce precursors of T lymphocytes, which seed the thymus thus becoming thymocytes and differentiate under influence of the Notch and its ligands. Still during the double negative stage, CD34 expression stops and Mature double is expressed.
This eliminates thymocytes with gross defects introduced into the Mature double cell receptor by gene rearrangement. In order to be positively-selectedthymocytes will have to interact with several cell surface molecules, MHCto ensure reactivity and specificity.
This eliminates by a process called "death by neglect" those T cells which would be non-functional due to an inability to bind MHC. Negative selection is the active induction of apoptosis in thymocytes with a high affinity for self peptides or MHC.
This eliminates cells which would direct immune responses Mature double self-proteins in the periphery. Additional mechanisms of tolerance active in the periphery exist to silence these cells such as anergydeletion, and regulatory T cells. If these peripheral tolerance mechanisms also fail, autoimmunity may arise.
Thymocytes are ultimately derived from bone marrow hematopoietic progenitor cells [see hematopoietic Mature double cellhematopoiesis ] which reach the thymus through the circulation. Therefore, which progenitors Mature double the thymus is unknown. Currently Early Lymphoid Progenitors ELP are proposed to settle the thymus and are likely the precursors of at least some thymocytes.
Precursors enter the thymus at the cortico-medullary junction. Following thymus entry, progenitors proliferate to generate the ETP population. This step is following by the generation of DN2 thymocytes which migrate from the cortico-medullary junction toward the thymus capsule. DN3 thymocytes are generated at the subcapsular zone.
In addition to proliferation, Mature double and T lineage commitment occurs within the DN thymocyte population. Commitment, or loss of alternative lineage potentials such as myeloid, B, and NK lineage potentials Mature double, is dependent on Notch signalingand is complete by the DN3 stage. The ability of T cells to recognize foreign antigens is mediated by the T cell receptor TCRwhich is a surface protein able to recognize short protein sequences peptides that are presented on MHC.
The purpose of thymocyte development is to produce mature T cells with a diverse array of functional T cell receptors, through the process of TCR gene rearrangement. Unlike most genes, which have a stable Mature double in each cell which expresses them, the T cell receptor is made up of a series of alternative gene fragments. In order to create a functional T cell receptor, the double negative thymocytes use a series of DNA-interacting enzymes to clip the DNA and bring separate gene fragments together.
The outcome of this process is that each T cell receptor has a different sequence, due to different choice of gene fragments and the errors introduced Mature double the cutting and joining process see section on V D J recombination for more information on TCR rearrangement. The evolutionary advantage in having a large number of unique T cell receptors is that each T cell is capable of recognizing a different peptide, providing a defense against rapidly evolving pathogens.
TCR rearrangement occurs in two Mature double. The cellular disadvantage in the rearrangement process is that many of the combinations of the T cell receptor gene fragments are non-functional. To eliminate thymocytes which Mature double made a non-functional T cell receptoronly cells that have successfully rearranged the beta chain to produce a functional pre-TCR are allowed to develop Mature double the DN3 stage.
Cells that fail to produce a functional pre-TCR are eliminated by apoptosis.
This process is referred to as the beta-selection checkpoint. However, many of these T cell receptors will still be non-functional, due to an inability to bind MHC.
The next major stage of thymocyte development is positive selection, to Mature double only those thymocytes which have a T cell receptor capable of binding MHC. At this stage thymocytes upregulate both CD4 and CD8becoming double positive cells. Double positive thymocytes that have a T cell receptor capable of binding MHC class I or class II even with a weak affinity receive signalling through Mature double T cell receptor.
Some thymocytes are able to rescue failed positive selection by receptor editing rearrangement of the other T cell receptor allele to produce a new T cell receptor.
Lineage commitment occurs at the late stage of positive selection and works by downregulation of both CD4 and CD8 reducing the signal from the T Mature double receptor and then upregulation of CD4 only. Both of these thymocytes types are known as single positive thymocytes.
Success in positive selection allows the thymocyte to undergo a number of maturational changes during the transition to a single positive T cell. The single positive T cells upregulate the chemokine receptor CCR7, causing migration from the cortex to the medulla. Mature double this stage the key maturation process involves negative selection, the elimination of autoreactive thymocytes.
The key disadvantage in a gene rearrangement process for T cell receptors is that by random chance, some arrangements of gene fragments will create a T cell receptor capable of binding self-peptides presented on MHC class I or MHC class II.
If T Mature double bearing these T cell receptors were to enter the periphery, they would be capable of activating an immune response against self, resulting in autoimmunity. Negative selection is the process evolved to reduce this risk. During negative selection, all thymocytes with a high affinity for binding self peptides presented on MHC class I or class II are Mature double to upregulate BCL2L11a protein which drives apoptosis.
Cells which do not have a high affinity for Mature double survive negative selection.
At this stage, some cells are also selected to become regulatory T cellsusually cells which have an intermediate affinity for self-peptide. Negative selection can occur at the double positive stage in the cortex.
However the repertoire of peptides in the cortex is limited to those expressed by epithelial cells, and double positive cells are poor at undergoing negative selection. Therefore, the most important site Mature double negative selection is the medulla, once cells are at the single positive stage. In order to remove thymocytes reactive to peripheral organs, the transcription factors Aire and Fezf2 drive the expression Mature double multiple peripheral antigens, such as insulin, resulting in deletion of cells specific for those antigens.
Single positive thymocytes remain in the medulla for 1—2 weeks, surveying self-antigens to test for autoreactivity.
During this time they undergo final maturational changes, and Mature double exit the thymus using S1P and CCR7. Upon entry to the peripheral bloodstreamthe cells are considered mature T cells, and not thymocytes.
Additional mechanisms of peripheral Mature double active in the periphery exist to silence these cells such as anergydeletion, and regulatory T cells.
Thymus transplantation results in that T cells are taught to avoid reacting with donor antigens instead, and may still Mature double with many self-antigens in the body. Thymocytes that gain oncogenic mutations allowing uncontrolled proliferation can become thymic lymphomas.
Additionally, other non-T hematopoietic lineages can develop in the thymus, including B lymphocytes B cellsNatural Killer lymphocytes NK cells. However, the thymus is not Mature double source of B, NK, or myeloid development.
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The development of these cells in the thymus reflects the multipotent nature of hematopoitic prognitors that seed the thymus. From Wikipedia, the free encyclopedia. This article needs additional citations for verification. Please help improve this article by adding citations Mature double reliable sources. Unsourced material may be challenged and removed.
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