The role of extra-thymic AIRE-expressing cells (eTACs) in AIRE-propagated immune tolerance
Keywords: AIRE
COVID-19
autoantibodies

The autoimmune regulator (AIRE) is a facilitator of gene transcription found primarily in the thymus where its expression is localized primarily to mature medullary thymic epithelial cells (mTECs). AIRE modulates the promiscuous gene expression of tissue-restricted antigens (TRAs) and thus ensures that maturing T cells in the thymus are exposed to a broad array of peptides derived from self-antigens typically detected in peripheral tissues. Autoreactive thymocytes are deleted from the emerging repertoire upon high affinity recognition of TRAs, a process known as negative selection that consequently establishes central tolerance. The deletion of autoreactive thymocytes by mTECs is, however, incomplete, allowing a significant number of self-reactive T cells to mature fully and exit to the periphery. This unwanted “escape” necessitates the existence of peripheral tolerance mechanisms operative outside of the thymus that collectively prevent autoreactivity and thus the likelihood of overt autoimmune destruction of tissues. In addition to its expression in mTECs, AIRE is also detected in two distinct hematopoietic cell populations, namely activated thymic B cells and extra-thymic AIRE-expressing cells (eTACs). However, the function of AIRE in these cells in general and their role in maintaining peripheral T cell tolerance remain largely unexplored.
The results of my research provide experimental evidence that AIRE is expressed under physiological conditions in the peripheral lymph nodes of wildtype mice. To examine the functional importance of these cells, I assessed their ability to present exogenously added antigen in vitro and compared this capacity to that of professional antigen presenting cells. Antigen-loaded eTACs and conventional dendritic cells demonstrated a comparable capacity for activating antigen-specific T cells in vitro, indicating a potential role for eTACs in peripheral tolerance mechanisms. To better understand the contribution of AIRE to central and peripheral tolerance, I generated lineage-specific, loss-of-AIRE transgenic mouse strains. Loss of AIRE expression limited to only mTECs resulted in changes in thymocytes and peripheral T cells that were comparable to constitutively AIRE-deficient mice, including a spectrum of autoimmune manifestations. In aggregate, the experimental data here presents evidence that while eTACs are potentially capable of contributing to peripheral tolerance via the presentation of antigen to T cells, AIRE-expressing mTECs are the primary players in AIRE-regulated immune tolerance.
Finally, due to the observation of anti-cytokine autoantibodies in patients with AIRE-deficiency and the finding of heterozygous AIRE mutations in some patients with COVID-19, I assessed the sera/plasmas of healthy control individuals, patients with AIRE-deficiency, and COVID-19 patients for the presence of anti-cytokine autoantibodies. I found that neutralizing autoantibodies against type I interferons are a risk factor for developing life-threatening COVID-19. These findings provide an explanation for some of the clinical variability observed in COVID-19 patients and pave the way for prevention and treatment when autoantibodies are identified early in the course of disease.