Abstract Objective We aim to explore the role of mechanistic target of rapamycin complex (mTORC) 2 in systemic lupus erythematosus (SLE) development, the in vivo regulation of mTORC2 by type I interferon (IFN) signaling in autoimmunity, and to use mTORC2 targeting therapy to ameliorate lupus-like symptoms in an in vivo lupus mouse model and an in vitro coculture model using human PBMCs. Method We first induced lupus-like disease in T cell specific Rictor , a key component of mTORC2, deficient mice by topical application of imiquimod (IMQ) and monitored disease development. Next, we investigated the changes of mTORC2 signaling and immunological phenotypes in type I IFNAR deficient Lpr mice. We then tested the beneficial effects of anti- Rictor antisense oligonucleotide ( Rictor -ASO) in a mouse model of lupus: MRL/ lpr mice. Finally, we examined the beneficial effects of RICTOR -ASO on SLE patients’ PBMCs using an in vitro T-B cell coculture assay. Results T cell specific Rictor deficient mice have reduced age-associated B cells, plasma cells and germinal center B cells, and less autoantibody production than WT mice following IMQ treatment. IFNAR1 deficient Lpr mice have reduced mTORC2 activity in CD4 + T cells accompanied by restored CD4 + T cell glucose metabolism, partially recovered T cell trafficking, and reduced systemic inflammation. In vivo Rictor -ASO treatment improves renal function and pathology in MRL/ lpr mice, along with improved immunopathology. In human SLE (N = 5) PBMCs derived T-B coculture assay, RICTOR- ASO significantly reduce immunoglobulin and autoantibodies production (P &lt; 0.05). Conclusion Targeting mTORC2 could be a promising therapeutic for SLE.

Targeting mechanistic target of rapamycin complex 2 attenuates immunopathology in Systemic Lupus Erythematosus