UCSF

Multicellular organisms require complex adaptive immune systems to maintain host defense from pathogens, but such systems must be precisely controlled to distinguish self from non-self and prevent autoimmunity. The autoimmune regulator (Aire) gene, a key transcriptional regulator expressed in medullary thymic epithelial cells (mTECs), has been shown to be crucial for central tolerance by inducing tissue specific antigen (TSA) expression in mTECs. Interestingly, we and others have also found extrathymic Aire-expressing cells (eTACs) in the secondary lymphoid organs such as the spleen and lymph nodes. eTACs are hematopoietic antigen- presenting cells (APCs) and consist of two similar cell types: CCR7+ Aire-expressing migratory dendritic cells (AmDCs) and an Aire-high population co-expressing Aire and retinoic acid receptor–related orphan receptor γt (RORγt) that we termed Janus cells (JCs). Functionally, eTACs are capable of enforcing deletion and anergy on self-reactive T cells, and self-antigen expression in eTACs is sufficient to prevent autoimmunity. Single cell RNA and ATAC sequencing revealed the transcriptional and genomic symmetry between eTACs and mTECs. This potentially identifies a core program driven by Aire that may influence self-representation and tolerance across the spectrum of immune development. Outside of self-antigen tolerance, we also revealed the crucial role of RORγt+ eTACs in maintaining oral tolerance by inducing food antigen-specific regulatory T cells and suppressing follicular helper cells. In the absence of JCs, mice develop more severe delayed-typed hypersensitivity response against dietary allergens. Taken together, these findings reveal the identity of various eTAC populations and provides novel insights into the mechanisms of immune tolerance against self and innocuous dietary antigens. Understanding the biology of this population may have significance for a range of clinical applications from autoimmunity to tumor immunity to maternal-fetal tolerance.