Aryl hydrocarbon Receptor Activation in DCs Regulates thymic Function and Immune Tolerance Induction.

Abstract

Abstract The thymus is a primary immune organ that mediates central tolerance through proper education of developing thymocytes and contributes to peripheral tolerance via the production of thymic regulatory T cells (tTregs). Differentiation of thymocytes involves interactions with both thymic epithelial cells and antigen presenting cells including thymic dendritic cells (tDCs). The thymus is highly sensitive to dioxin, an environmental pollutant that is the prototypical ligand for the Aryl hydrocarbon receptor (AhR) and can induce severe thymic atrophy; however, the underlying mechanisms and ultimate consequences of AhR-mediated thymic atrophy are not currently defined. Moreover, determining how AhR activation in thymic DCs affects thymopoiesis and tTreg induction will further enhance our understanding of immune tolerance. We hypothesized that AhR activation in DCs blocks thymopoiesis and induces tTregs via increased CTLA-4 expression on tDCs. Using CD11ccre x AhRfx(AHRCD11c) conditional knockout mice, we observed that AhR deficiency in CD11c+ tDCs blocked dioxin-induced thymic atrophy and the generation of tTregs, an effect that occurred with other AhR ligands including ITE. Moreover, elevated CTLA-4 mRNA and protein expression was detected in CD11c+ tDCs suggesting a possible mechanism underlying these effects. Together, these findings support the premise that AhR activation in CD11c+ thymic DCs is a critical regulator of thymopoiesis, and the generation of central and peripheral immune tolerance. This research was supported by R01ES013784 (DMS) and NIH Diversity Supplement (SLC).