T cell

T cells are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor on their cell surface.
T cells are born from hematopoietic stem cells, found in the bone marrow. Developing T cells then migrate to the thymus gland to develop. T cells derive their name from the thymus. After migration to the thymus, getting stimulated by thymosin, the precursor cells mature into several distinct types of T cells. T cell differentiation also continues after they have left the thymus. Groups of specific, differentiated T cell subtypes have a variety of important functions in controlling and shaping the immune response.
One of these functions is immune-mediated cell death, and it is carried out by two major subtypes: CD8⁺ "killer" and CD4⁺ "helper" T cells. CD8⁺ T cells, also known as "killer T cells", are cytotoxic – this means that they are able to directly kill virus-infected cells, as well as cancer cells. CD8⁺ T cells are also able to use small signalling proteins, known as cytokines, to recruit other types of cells when mounting an immune response. A different population of T cells, the CD4⁺ T cells, function as "helper cells". Unlike CD8⁺ killer T cells, the CD4⁺ helper T cells function by further activating memory B cells and cytotoxic T cells, which leads to a larger immune response. The specific adaptive immune response regulated by the T_H cell depends on its subtype, which is distinguished by the types of cytokines they secrete.
Regulatory T cells are yet another distinct population of T cells that provide the critical mechanism of tolerance, whereby immune cells are able to distinguish invading cells from "self". This prevents immune cells from inappropriately reacting against one's own cells, known as an "autoimmune" response. For this reason, these regulatory T cells have also been called "suppressor" T cells. These same regulatory T cells can also be co-opted by cancer cells to prevent the recognition of, and an immune response against, tumor cells.

Development

Origin, early development and migration to the thymus

All T cells originate from c-kit⁺Sca1⁺ haematopoietic stem cells which reside in the bone marrow. In some cases, the origin might be the foetal liver during embryonic development. The HSC then differentiate into multipotent progenitors which retain the potential to become both myeloid,and lymphoid cells. The process of differentiation then proceeds to a common lymphoid progenitor, which can only differentiate into T, B or NK cells. These CLP cells then migrate via the blood to the thymus, where they engraft:. Henceforth they are known as thymocytes, the immature stage of a T cell.
The earliest cells which arrived in the thymus are commonly termed double-negative, as they express neither the CD4 nor CD8 co-receptor. The newly arrived CLP cells are CD4⁻CD8⁻CD44⁺CD25⁻ckit⁺ cells, and are termed early thymic progenitor cells. These cells will then undergo a round of division and downregulate c-kit and are termed double-negative one cells. To become T cells, the thymocytes must undergo multiple DN stages as well as positive selection and negative selection.
Double negative thymocytes can be identified by the surface expression of CD2, CD5 and CD7. Still during the double negative stages, 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.

TCR development

A critical step in T cell maturation is making a functional T cell receptor. Each mature T cell will ultimately contain a unique TCR that reacts to a random pattern, allowing the immune system to recognize many different types of pathogens. This process is essential in developing immunity to threats that the immune system has not encountered before, since due to random variation there will always be at least one TCR to match any new pathogen.
A thymocyte can only become an active T cell when it survives the process of developing a functional TCR. The TCR consists of two major components, the alpha and beta chains. These both contain random elements designed to produce a wide variety of different TCRs, but due to this huge variety they must be tested to make sure they work at all. First, the thymocytes attempt to create a functional beta chain, testing it against a 'mock' alpha chain. Then they attempt to create a functional alpha chain. Once a working TCR has been produced, the cells then must test if their TCR will identify threats correctly, and to do this it is required to recognize the body's major histocompatibility complex in a process known as positive selection. The thymocyte must also ensure that it does not react adversely to "self" antigens, called negative selection. If both positive and negative selection are successful, the TCR becomes fully operational and the thymocyte becomes a T cell.

TCR β-chain selection

At the DN2 stage, cells upregulate the recombination genes RAG1 and RAG2 and re-arrange the TCRβ locus, combining V-D-J recombination and constant region genes in an attempt to create a functional TCRβ chain. As the developing thymocyte progresses through to the DN3 stage, the thymocyte expresses an invariant α-chain called pre-Tα alongside the TCRβ gene. If the rearranged β-chain successfully pairs with the invariant α-chain, signals are produced which cease rearrangement of the β-chain. Although these signals require the pre-TCR at the cell surface, they are independent of ligand binding to the pre-TCR. If the chains successfully pair a pre-TCR forms, and the cell downregulates CD25 and is termed a DN4 cell. These cells then undergo a round of proliferation, and begin to re-arrange the TCRα locus during the double-positive stage.

Positive selection

The process of positive selection takes 3 to 4 days and occurs in the thymic cortex. Double-positive thymocytes migrate deep into the thymic cortex, where they are presented with self-antigens. These self-antigens are expressed by thymic cortical epithelial cells on MHC molecules, which reside on the surface of cortical epithelial cells. Only thymocytes that interact well with MHC-I or MHC-II will receive a vital "survival signal", while those that cannot interact strongly enough will receive no signal and die from neglect. This process ensures that the surviving thymocytes will have an 'MHC affinity' that means they will exhibit stronger binding affinity for specific MHC alleles in that organism. The vast majority of developing thymocytes will not pass positive selection, and die during this process.
A thymocyte's fate is determined during positive selection. Double-positive cells that interact well with MHC class II molecules will eventually become CD4⁺ "helper" cells, whereas thymocytes that interact well with MHC class I molecules mature into CD8⁺ "killer" cells. A thymocyte becomes a CD4⁺ cell by down-regulating expression of its CD8 cell surface receptors. If the cell does not lose its signal, it will continue downregulating CD8 and become a CD4⁺, both CD8⁺ and CD4⁺ cells are now single positive cells.
This process does not filter for thymocytes that may cause autoimmunity. The potentially autoimmune cells are removed by the following process of negative selection, which occurs in the thymic medulla.

Negative selection

Negative selection removes thymocytes that are capable of strongly binding with "self" MHC molecules. Thymocytes that survive positive selection migrate towards the boundary of the cortex and medulla in the thymus. While in the medulla, they are again presented with a self-antigen presented on the MHC complex of medullary thymic epithelial cells. mTECs must be Autoimmune regulator positive to properly express tissue-specific antigens on their MHC class I peptides. Some mTECs are phagocytosed by thymic dendritic cells; this makes them AIRE⁻ antigen presenting cells, allowing for presentation of self-antigens on MHC class II molecules. Thymocytes that interact too strongly with the self-antigen receive an apoptotic signal that leads to cell death. However, some of these cells are selected to become T_reg cells. The remaining cells exit the thymus as mature naive T cells, also known as recent thymic emigrants. This process is an important component of central tolerance and serves to prevent the formation of self-reactive T cells that are capable of inducing autoimmune diseases in the host.

TCR development summary

β-selection is the first checkpoint, where thymocytes that are able to form a functional pre-TCR are allowed to continue development in the thymus. Next, positive selection checks that thymocytes have successfully rearranged their TCRα locus and are capable of recognizing MHC molecules with appropriate affinity. Negative selection in the medulla then eliminates thymocytes that bind too strongly to self-antigens expressed on MHC molecules. These selection processes allow for tolerance of self by the immune system. Typical naive T cells that leave the thymus are self-restricted, self-tolerant, and single positive.

Thymic output

About 98% of thymocytes die during the development processes in the thymus by failing either positive selection or negative selection, whereas the other 2% survive and leave the thymus to become mature immunocompetent T cells.
The thymus contributes fewer cells as a person ages. As the thymus shrinks by about 3% a year throughout middle age, a corresponding fall in the thymic production of naive T cells occurs, leaving peripheral T cell expansion and regeneration to play a greater role in protecting older people.