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

Objective: We aim to explore the role of mechanistic target of rapamycin complex (mTORC) 2 in systemic lupus erythematosus (SLE) development, the in regulation of mTORC2 by type I interferon (IFN) signaling in autoimmunity, and to use mTORC2 targeting therapy to ameliorate lupus-like symptoms in an lupus mouse model and an coculture model using human PBMCs.

Method: We first induced lupus-like disease in T cell specific , 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- antisense oligonucleotide (-ASO) in a mouse model of lupus: MRL/ mice. Finally, we examined the beneficial effects of -ASO on SLE patients' PBMCs using an T-B cell coculture assay.

Results: T cell specific 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. -ASO treatment improves renal function and pathology in MRL/ mice, along with improved immunopathology. In human SLE (N = 5) PBMCs derived T-B coculture assay, ASO significantly reduce immunoglobulin and autoantibodies production (P < 0.05).

Conclusion: Targeting mTORC2 could be a promising therapeutic for SLE.