Induction of autoimmune disease by adoptive transfer of an atypical NK cell subset (BA7P.147)

Abstract Several mouse models of SLE, including FcgRIIB-KO and TLR7tg mice, develop an expansion of an atypical NK cell subset with functional similarity to cells referred as IKDCs or pre-mNKs in other systems and identified as NK1.1+CD11c+CD122+MHC-II+. These cells belong to the NK cell lineage because they depend on IL15 and express E4BP4. Functionally they are cytotoxic, produce type I and type II interferons upon activation and they are efficient antigen presenting cells both through MHC-II expression and in cross-presentation to CD8s. These atypical NK cells are responsive to TLR stimulation and thus are most abundant in mice with high copy number of the Tlr7 gene. They are highly proliferative as assessed by in vivo BrdU incorporation. Transferring 4 million atypical NKs purified from spleens of SLE-prone mice into WT induces a 2-week-long wave of inflammatory cytokines in the serum, a sustained increase in T cell activation and follicular helper cells for the following months, and a progressive expansion of dendritic cells, monocytes and granulocytes. Furthermore IL15 deficiency, which impedes development of NK cells, ameliorates the autoimmune pathology of TLR7tg mice. These results suggest that cells of the NK lineage can develop into cytokine producing/antigen-presenting cells that affect the priming and progression of systemic autoimmune disease.