T cells are able to recognize foreign antigens and contribute to disease protection, and yet they are tolerant to the myriad of self-antigens they are exposed to. Tolerance to self-antigens is developed in two ways — central tolerance to ubiquitously expressed proteins and blood-borne self-antigens occurs in the thymus, and peripheral mechanisms are required for the development of tolerance to self-antigens that are expressed in specific tissues. However, tissue-specific antigens have been detected within the thymus. The cells responsible for this 'promiscuous' gene expression have, until now, been undefined. Reporting in Nature Immunology, Derbinski and colleagues now show that medullary thymic epithelial cells (mTECs) express a range of tissue-specific antigens in the thymus.

To investigate gene expression within the thymus the authors purified cortical and medullary TECs, macrophages and dendritic cells and analysed their gene expression profiles by reverse-transcription polymerase chain reaction (RT-PCR). The expression of a range of genes (including enzymes, structural proteins and genes of restricted tissue distribution) was studied. mTECs consistently expressed a wide range of tissue-specific self-antigens.

Further experiments showed that the scope and level of promiscuous gene expression by mTECs was maintained throughout the period of thymic T-cell output and did not decline with age. This is important, for if the expression of tissue-specific genes in the thymus is to shape the T-cell repertoire it needs to be maintained as long as T cells are being produced.

The authors also showed that the ability of mTECs to express self-antigens is not dependent on intact T-cell development and is a cell-autonomous property of mTECs.

But is this promiscuous gene expression important in the generation of tolerant T cells? To address this question, Derbinksi and colleagues generated chimeric mice for serum amyloid P component (Sap), the main acute-phase protein in mice. Mice either expressed Sap within mTECs exclusively (Sap+/+ thymus transplanted into thymectomized Sap−/− recipients) or Sap expression by mTECs was excluded (a Sap−/− thymus transplanted into thymectomized Sap+/+ recipient). The results showed that for Sap, promiscuous expression in mTECs was sufficient, but not necessary, to induce CD4+ T-cell tolerance.

In conclusion, the authors describe the thymus as an immunological homunculus, in that it expresses a range of randomly selected self-antigens that mirror and anticipate the peripheral self.