Thymocyte
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.
This eliminates (by a process called "death by neglect") those T cells which would be non-functional due to an inability to bind MHC.
Additional mechanisms of peripheral tolerance exist to silence these cells, but if these fail, autoimmunity may arise.
Thymocytes are classified into a number of distinct maturational stages based on the expression of cell surface markers.
They produce precursors of T lymphocytes, which seed the thymus (thus becoming thymocytes) and differentiate under influence of the Notch protein and its ligands.
In order to be positively-selected, thymocytes will have to interact with several cell surface molecules, MHC, to 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 not 100% effective, some autoreactive T cells escape thymic censorship, and are released into the circulation.
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 cellular disadvantage in the rearrangement process is that many of the combinations of the T cell receptor gene fragments are non-functional.
[11][12] Following β-selection thymocytes generate CD4+CD8+ double positive cells, which then undergo TCRα rearrangement, resulting in completely assembled TCR.
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 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.
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 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.
[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.
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.
