Thymocyte

A thymocyte is an immune cell present in the thymus, before it undergoes transformation into a T cell.^[1] Thymocytes are produced as stem cells in the bone marrow and reach the thymus via the blood.

Thymopoiesis describes the process which turns thymocytes into mature T cells according to either negative or positive selection. This selection process is vitally important in shaping the population of thymocytes into a peripheral pool of T cells that are able to respond to foreign pathogens but remain tolerant towards the body's own antigens. Positive selection selects cells which are able to bind MHC class I or II molecules with at least a weak affinity. 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 destroys 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% effective, and some autoreactive T cells escape and are released into the circulation. Additional mechanisms of peripheral tolerance exist to silence these cells, but if these fail, autoimmunity may arise.

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 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).

In mice

In humans

In humans, circulating CD34+

Early, double negative thymocytes express (and can be identified by) CD2, CD5 and CD7. Still during the double negative stage, CD34 expression stops and CD1 is expressed. Expression of both CD4 and CD8 makes them double positive, and matures into either CD4+ or CD8+ cells.^[2]

Events during maturation

type:	functional (beta selection)	functional (positive selection)	autoreactive (negative selection)
location:	cortex	cortex	cortex/medulla
	In order to pass the β-selection checkpoint, the β chain of the T cell receptor by gene rearrangement.	In order to be positively-selected, thymocytes will have to interact with several cell surface molecules, MHC, to ensure reactivity and specificity.[3] Positive selection selects cells with a T cell receptor able to bind MHC class I or II molecules with at least a weak affinity. 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 towards self-proteins in the periphery. Negative selection is not 100% effective, 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 regulatory T cells. If these peripheral tolerance mechanisms also fail, autoimmunity may arise.

Thymus settling

Thymocytes are ultimately derived from bone marrow hematopoietic progenitor cells [see

The ability of T cells to recognize foreign antigens is mediated by the

In the β-selection stage similarly to the mature TCR, pre-TCR also forms an immunological synapse.[8] Although the pre-TCR and the peptide-bound MHC interaction is not essential for T cell development,^[9][10] it plays a critical role in encouraging the preferential proliferation of cells whose pre-TCR can bind self-MHC.^[11][12]

Following β-selection thymocytes generate CD4+CD8+ double positive cells, which then undergo TCRα rearrangement, resulting in completely assembled TCR.

Positive selection and lineage commitment

Thymocytes which pass β-selection express a

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 the T cell receptor.[3] 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).

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 recognize MHC class I, and they downregulate 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.

The key disadvantage in a gene rearrangement process for

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 transcription factors Aire and Fezf2 drive the expression of multiple peripheral antigens, such as insulin, resulting in deletion of cells specific for those antigens.^[13][14] 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

Negative selection is not 100% effective, some autoreactive T cells escape thymic censorship, and are released into the circulation. Additional mechanisms of

Thymus transplantation results in that T cells are taught to avoid reacting with donor antigens instead, and may still react with many self-antigens in the body. Autoimmune disease is a frequent complication after thymus transplantation, found in 42% of subjects over 1 year post-transplantation.^[15] However, this is partially explained by that the indication itself, that is, complete DiGeorge syndrome (absence of thymus), increases the risk of autoimmune disease.^[16]

Cancer

Thymocytes that gain oncogenic mutations allowing uncontrolled proliferation can become thymic

Alternative lineages

As well as classical αβ T cells (their development of which is outlined above), a number of other T lineages develop in the thymus, including γδ T cells and Natural Killer T (NKT)cells. Additionally, other non-T hematopoietic lineages can develop in the thymus, including B lymphocytes (B cells), Natural Killer lymphocytes (NK cells).^[17][18]), myeloid cells, and dendritic cells. However, the thymus is not a source of B, NKC, or myeloid development (this statement is not true for all B-cells or NKC). The development of these cells in the thymus reflects the multi-potent nature of hematopoietic progenitors that seed the thymus. Mature B-cells and other APCs can also be found in the medulla which contribute to negative selection processes.^[19]

References