Role of NK cells in TLR7-induced systemic autoimmune disease (93.30)

Abstract

Abstract An inappropriate activation of innate immune pathways can lead to systemic autoimmune disease, as illustrated by the phenotype of TLR7-overexpressing transgenic mice characterized by anti-RNA antibody production, glomerulonephritis, anemia, and a pro-inflammatory interferon signature in B cells and dendritic cells. Mixed bone marrow reconstitution experiments show that NK cells expand in TLR7tg because of the NK cell intrinsic sensitivity to TLR7 stimulation. NK cells in TLR7tg mice have an unusual phenotype: most NK1.1+ cells are DX5-, CD11c+ even though they have been confirmed to be bona fide NK cells by their cytotoxic responses and lack of T cell specific markers. In vitro stimulation of TLR7tg NK cells with TLR7 agonists induced production of TNFα, MCP-1, IFNγ and particularly IL-10. To assess the function of NK cells in developing the TLR7-induced autoimmune inflammatory condition, we have bred our TLR7tg mice to IL15-deficient mice IL-15 is necessary for development of NK cells and memory CD8 cells. We have observed that in the absence of IL15 some of the pro-inflammatory subsets such as CD11c+NK cells, Ly6C+monocytes, granulocytes, conventional DCs and memory T cells are reduced compared to TLR7tg. On the other hand, spontaenous germinal centers and lymphocyte activation occur at the same rate in the absence of IL15. This results suggest that the development of spontaneous autoreactive germinal centers is independent from the myeloid expansion in TLR7tg mice.