The Gardner lab studies novel mechanisms of immune tolerance and their applications in autoimmunity, transplantation, and cancer immunology. In particular we focus on the biology and function of a unique population of dendritic cells expressing the Autoimmune Regulator (Aire) gene.
Previously the lab has shown that by using bacterial artificial chromosome (BAC) transgenesis we could exploit the Aire promoter to drive expression of disease-relevant antigens and transcriptional reporters in mice. Using these tools, we were able to alter thymic negative selection against disease-relevant antigens, but we were also able to identify novel populations of Aire-expressing cells outside the thymus in the secondary and tertiary lymphoid organs - which we called extra-Thymic Aire-expressing Cells (eTACs). We have since gone on to describe some of the fundamental biology and immunology of this population.
We have found that, as in the thymus, Aire in eTACs regulates the expression of an array of tissue-specific antigens, though the set of antigens may be distinct from those expressed in the thymus. Further, we were able to demonstrate that eTACs could form long-term interactions with cognate T cells, and that the result of those interactions was deletional tolerance.
We subsequently demonstrated that eTACs were hematopoietic in origin and members of the dendritic cell family, were highly potent inducers of self-tolerance resistant to both innate inflammatory stimuli and costimulation, and that antigen expression in eTACs was sufficient to prevent insulitis and autoimmune diabetes in a murine adoptive transfer model.
We are currently using multimodal approaches from single-cell RNA-sequencing to ATAC-Seq to novel transgenic tools to understand the biology and immunology of this unique population of cells with significant potential for clinical relevance. We are interested in the role of such tolergenic APCs in normal immune homeostasis, as well as in disease-relevant applications from transplantation to tumor immunity.