Optineurin modulates mTORC2/AKT/STAT3 signaling to control MHC class II expression and adaptive immunity against HSV-1.

Herpes simplex virus 1 (HSV-1) infection contributes to immunopathogenic diseases and lacks an effective vaccine. Improving antigen presentation is key to better vaccine strategies and more robust immune responses. Here, we show that optineurin (OPTN), an autophagy receptor traditionally involved in protein recycling, unexpectedly stabilizes RICTOR (mechanistic target of rapamycin complex 2 [mTORC2]), a crucial step in enhancing MHC class II surface expression in dendritic cells. OPTN regulates the AKT/mTOR/signal transducer and activator of transcription 3 (STAT3) pathway, with the AKT2 isoform playing a central role. Using single-cell RNA sequencing (scRNA-seq) and transgenic mouse models, we identify the mechanistic details of this pathway. Dysregulation impairs antigen presentation, weakening immunity and vaccine efficacy. Our findings uncover a previously unknown function of OPTN and highlight its role in coordinating innate and adaptive immune defenses, with implications for vaccine development and immune response modulation in HSV-1 and other viral and bacterial diseases.