T lymphocytes like B lymphocytes are puzzle masters that stick their receptors together in innumerable ways which is called recombination. Being free to choose from gene pieces and not concerned which receptor is finally built in a cell, it is inevitable that there are generated lymphocytes which recognize self-determinants and might attack the very same organism if not silenced from the beginning. T lymphocytes learn in the thymus to discriminate between self and non-self and only non-self reactive T cells are to leave the thymus to become eventually effector cells of the immune system, otherwise autoimmunity will develop.

The process by which any self peptide is presented to T cells has been a riddle for a long time.  From the 2000s on the riddle was partially solved: There is stochastic expression of tissue restricted selfantigens in medullary thymic epithelial cells (mTec) under the control of the AIRE protein. (See AIRE in OMIN). Stochastic means that the antigens are randomly expressed, only some in a given cell, but obviously all self antigens at a given time since autoimmunity is rare. This is achieved by an random epigenetic activation of genes. These proteins are then processed and their peptides loaded into the peptide pockets of major histocompatibility proteins class I (MHC class I). The peptides are presented in these MHC class I to the T cells which become silent once they recognize any of this peptides in self MHC. This mechamism has been about for almost 10 years.

A recent paper in Cell by Japanese colleagues adds a second mechanism to central tolerance. This time it is the Fezf2 that directs a mechanism of promiscuous gene activation. And as in the case of AIRE the lack of Fezf2 leads to autoimmune disease since autoimmune T cells are not silenced in the thymus. Fezf2 is regulated by the lymphotoxin-beta receptor. It is striking that there are genes activated by AIRE while others are stimulated by Fezf2.

After 10 years of AIRE in the air Fezf2 is a welcomed addition to the puzzle autoimmunity still presents.

Highly recommended.