In addition to a TEC subpopulation in the thymus, AIRE was also reported to be expressed in rare cell population in secondary lymphoid organs. However, the identity and functional significance of these AIRE-expressing extrathymic cells (eTACs) have remained elusive. Recently, we have provided critical insights into the molecular characteristics and functional significance of this mystery eTAC population. Specifically, we discovered that they are part of a previously uncharacterized family of antigen presenting cells (APCs), which is distinct from conventional APCs, such as dendritic cells, macrophages and innate lymphoid cells and is characterized by the expression of RORyT transcription factor (reviewed in Abramson J, et al Nat Rev Immunol, 2023). More importantly, however, we found that these AIRE+RORyT+ APCs are endowed with the capacity to sense, internalize and present Candida albicans, a fungus that is known to cause chronic infections in AIRE deficient patients. More importantly, our recent study revealed that eTAC-specific deletion of AIRE results in impaired generation of candida-specific Th17 cell clones and consequently to increased susceptibility to Candida albicans infection (Dobes J, et al, Nature Immunol. 2022). Collectively, these findings not only highlight a novel and additional functional role for AIRE, but more importantly identify previously uncharacterized regulatory mechanism underlying an effective defense response against fungal infections. Currently, we are trying to address multiple open questions regarding this newly identified RORyT+ eTAC population, including their exact lineage identity and cellular plasticity, mechanisms controlling their differentiation, and additional functional roles in the immune system.
