Thymocytes are T cell precursors which develop in the thymus. The processes of beta-selection, positive selection and negative selection shape thymocytes into a peripheral pool of T cells that are able to respond to foreign pathogens and are immunologically tolerant towards self antigens. T cells are a subset of lymphocytes that play a large role in the immune response. ... In human anatomy, the thymus is an organ located in the upper anterior portion of the chest cavity. ...

Stages of maturation

Thymocytes are classified into a number of distinct maturational stages based on the expression of cell surface markers. The earliest thymocyte stage is the double negative stage (negative for both CD4 and CD8), 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).

Events during maturation

type:	functional (beta selection)	functional (positive selection)	autoreactive (negative selection)
location:	cortex	cortex	cortex/medulla
	In order to pass the beta-selection point, the beta chain of the T cell receptor rearranged by the thymocyte must retain the structural properties allowing it to be presented on the surface of the thymocyte with pre-TCRalpha. This eliminates thymocytes with gross defects introduced into the T cell receptor by gene rearrangement. Image File history File links Download high-resolution version (3117x4230, 1190 KB) File links The following pages on the English Wikipedia link to this file (pages on other projects are not listed): Thymus Cytotoxic T cell ... The T cell receptor or TCR is responsible for recognizing antigen bound to Major histocompatibility complex (MHC). ... The T cell receptor or TCR is responsible for recognizing antigen bound to Major histocompatibility complex (MHC). ...	In order to be positively-selected, thymocytes will have to interact with several cell surface molecules, MHC/HLA, to ensure reactivity and specificity[1]. Postive selection selects cells with a T cell receptor able to bind MHC class I/II or peptide molecules with at least a weak affinity. This eliminates (by a process called "death by neglect") those T cells which would not be non-functional due to an inability to bind MHC. The T cell receptor or TCR is responsible for recognizing antigen bound to Major histocompatibility complex (MHC). ... MHC I (1hsa) vs MHC II (1dlh) (more details. ... Peptides (from the Greek πεπτος, digestible), are the family of short molecules formed from the linking, in a defined order, of various α-amino acids. ...	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 towards self-proteins in the periphery. Negative selection is not 100% complete, some autoreactive T cells escape thymic censorship, and are released into the circulation. Additional mechanisms of tolerance active in the periphery exist to silence these cells such as anergy, deletion, and regulatory T cells. If these central tolerance mechanisms also fail, autoimmunity may arise. Anergy is a theory in immunobiology in which there is a lack of reaction by the bodys defence mechanisms when foreign substances come into contact with the body. ... This article or section should be merged with suppressor T cell Regulatory T cells (also known as suppressor T cells) are characterised by virtue of their expression of the cell surface markers CD4 and CD25. ... Central tolerance is a condition caused by tumor cells caused by tumor antigens inhibiting the immune system which has no reaction. ... Autoimmunity is the failure of an organism to recognize its own constituent parts (down to the sub-molecular levels) as self, which results in an immune response against its own cells and tissues. ...

Thymocyte entry

The precursor to the thymocyte population is a rare hematopoietic progenitor, which develops in the bone-marrow and enters the thymus through the circulation. ^[2]. The precursors proliferate rapidly in the microenvironment (dependent on c-kit and the cytokine milieu) to generate a large population of double negative thymocytes. Precurors enter the thymus at the cortex-medulla junction, and migrate deep into the cortex using the chemokine receptor CXCR4. Chemokines are a family of pro-inflammatory activation-inducible cytokines, or small protein signals secreted by cells. ...

Beta selection

Histology of the thymus showing the cortex and medulla

Minute structure of thymus.

The ability of T cells to recognise foreign antigens is mediated by the T cell receptor, which is a surface protein able to recognise short protein sequences (peptides) that are presented on MHC. During the double negative stage the major maturation step of thymocytes is to express a T cell receptor. Image File history File links Thymus. ... Image File history File links Thymus. ... The T cell receptor or TCR is responsible for recognizing antigen bound to Major histocompatibility complex (MHC). ... Peptides are the family of molecules formed from the linking, in a defined order, of various amino acids. ... MHC I (1hsa) vs MHC II (1dlh) (more details. ... The T cell receptor or TCR is responsible for recognizing antigen bound to Major histocompatibility complex (MHC). ...

Unlike most genes, which have a stable sequence 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 during the cutting and joining process. The evolutionary advantage in having a large number of unique T cell receptors is that each T cell is capable of recognising a different peptide, providing a defence against rapidly evolving pathogens. ^[3]. The T cell receptor or TCR is responsible for recognizing antigen bound to Major histocompatibility complex (MHC). ... The T cell receptor or TCR is responsible for recognizing antigen bound to Major histocompatibility complex (MHC). ... The T cell receptor or TCR is responsible for recognizing antigen bound to Major histocompatibility complex (MHC). ...

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 have made a non-functional T cell receptor, the beta-selection point is required before T cells can advance from the double negative to the double positive stage. The beta-selection point requires that the first T cell receptor gene to be arranged (T cell receptor beta) is capable to binding a pre-T cell receptor alpha protein and assembling on the surface with the signalling proteins. Thymocytes which fail this "beta selection" die by apoptosis. The T cell receptor or TCR is responsible for recognizing antigen bound to Major histocompatibility complex (MHC). ... The T cell receptor or TCR is responsible for recognizing antigen bound to Major histocompatibility complex (MHC). ...

Positive selection and lineage commitment

Thymocytes which pass "beta selection" express a T cell receptor which is capable of assembling on the surface. 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 keep only those thymocytes which have a T cell receptor capable of binding MHC. The T cell receptor requires CD4 as a coreceptor to bind to MHC class I, and CD8 as a coreceptor to bind MHC class II. At this stage thymocytes upregulate both CD4 and CD8, becoming double positive cells. The T cell receptor or TCR is responsible for recognizing antigen bound to Major histocompatibility complex (MHC). ... The T cell receptor or TCR is responsible for recognizing antigen bound to Major histocompatibility complex (MHC). ...

Double positive thymocytes that have a T cell receptor capable of binding MHC class I or class II with even a weak affinity receive signalling through the T cell receptor. ^[4]. Thymocytes that have a T cell receptor incapable of binding MHC class I or class II undergo apoptosis. 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). A cell undergoing apoptosis. ...

The double positive thymocytes undergo lineage commitment, maturing into a CD8+ T cell (recognising MHC class I) or a CD4+ T cell (recognising MHC class II). 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 cell receptor) and then upregulation of CD4 only. Thymocytes that start receiving signal again are those that recognise MHC class II, and they become CD4+ T cells. Thymocytes that do not start receiving signal again are those that recognise MHC class I, and they downregulation CD4 and upregulate CD8, to become CD8+ T cells. Both of these thymocytes types are known as single positive thymocytes.

Negative selection

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. At this stage the key maturation process involves negative selection, the elimination of autoreactive thymocytes. Chemokines are a family of pro-inflammatory activation-inducible cytokines, or small protein signals secreted by cells. ...

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 cells 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 induced to upregulate Bim, a protein which drives apoptosis. Cells which do not have a high affinity for self ('safe' cells) survive negative selection. The T cell receptor or TCR is responsible for recognizing antigen bound to Major histocompatibility complex (MHC). ... Autoimmunity is the failure of an organism to recognize its own constituent parts (down to the sub-molecular levels) as self, which results in an immune response against its own cells and tissues. ...

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 for negative selection is the medulla, once cells are at the single positive stage. In order to remove thymocytes reactive to peripheral organs, the gene AIRE drives the expression of multiple peripheral antigens, such as insulin, creating an "immunological self-shadow". ^[5][6] This allows single positive thymocytes to be exposed to a more complex set of self-antigens than is present in the cortex, and therefore more efficiently deletes those T cells which are autoreactive.

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 then exit the thymus using S1P and CCR7. Upon entry to the peripheral bloodstream, the cells are considered mature T cells, and not thymocytes. Red blood cells (erythrocytes) are present in the blood and help carry oxygen to the rest of the cells in the body Blood is a circulating tissue composed of fluid plasma and cells (red blood cells, white blood cells, platelets). ...

Cancer

Thymocytes that gain oncogenic mutations allowing uncontrolled proliferation can become thymic lymphomas. Lymphoma is a general term for cancers that develop in the lymphatic system. ...

Alternative lineages

As well as classical T cells, a number of alternative cell lineages develop in the thymus, including gamma-delta T cells, Natural Killer T cells and lymphoid dendritic cells.

References

1. ^ Baldwin TA, Hogquist KA, Jameson SC, The fourth way? Harnessing aggressive tendencies in the thymus. “J Immunol.” 173:6515-20, 2004. http://www.jimmunol.org/cgi/content/full/173/11/6515]
2. ^ Schwarz BA, Bhandoola A. Trafficking from the bone marrow to the thymus: a prerequisite for thymopoiesis. Immunol Rev 209:47, 2006. full text
3. ^ Sleckman BP, Lymphocyte antigen receptor gene assembly: multiple layers of regulation. Immunol Res 32:153-8, 2005. full text
4. ^ Baldwin TA, Hogquist KA, Jameson SC, The fourth way? Harnessing aggressive tendencies in the thymus. “J Immunol.” 173:6515-20, 2004. http://www.jimmunol.org/cgi/content/full/173/11/6515]
5. ^ Anderson, M.S. et al. (2002) Projection of an Immunological Self-Shadow Within the Thymus by the Aire Protein. Science 298 (5597), 1395-1401
6. ^ Liston, A. et al. (2003) Aire regulates negative selection of organ-specific T cells. Nat Immunol 4 (4), 350-354