Autoimmune rheumatologic diseases
Understanding the mechanisms underlying the balance between regulatory and pathogenic CD4+ T cell generation will accelerate therapeutic target identification in autoimmune diseases such as Systemic Lupus Erythematosus (SLE), where this balance is dysregulated. We recently described that in vitro priming of naïve CD4+ T cells with plasmacytoid DCs (pDCs) activated with either CpGA or Oxidized mitochondrial DNA (Ox mtDNA) leads to the generation of Type 1 regulatory T cells (Tr1) or Th10 cells, respectively. Th10 cells are expanded in the blood of SLE patients and accumulate within the tubuloinsterstitial areas of proliferative nephritis (PLN) lesions. These cells produce IL10 and mitochondrial ROS (mtROS) as the result of reverse electron transport (RET) fueled by the tricarboxylic acid (TCA) cycle intermediate succinate. Functionally, Th10 cells are not suppressive, but they provide B cell help through the synergistic effect of IL10 and succinate.
The mechanisms responsible for the acquisition of a regulatory versus helper phenotype upon priming CD4+ T cells with pDCs activated with two different classes of TLR9 ligands remained elusive. We now show that the generation of Th10 cells in response to Ox mtDNA-activated pDCs requires the activation of the Delta Like Canonical Notch Ligand 4 (Dll4)-Notch pathway. Conversely, CpGA-activated pDCs drive the generation of Tr1 through the upregulation and activation of the TLR7-IRF7 pathway on naïve CD4+ T cells. These data carry important therapeutic implications for the identification of therapeutic targets in SLE and beyond.