PEP-R619W Distinctly Modulates Persistent Type-I Interferon Signaling to enhance DC and CD8 T cell function 4147

Description Persistent Type I interferon (IFN-I) signaling contributes to chronic viral infections by driving dendritic cell (DC) dysfunction and T cell exhaustion. The autoimmune-associated protein PEP-R619W alters immune responses, but its role in viral infections remains poorly defined. We hypothesize that PEP-R619W enhances antiviral immunity by modulating IFN-I signaling and boosting DC immunostimulatory protein expression. Using CRISPR/Cas9-engineered PEP-R619W mice, we show that these mice clear Lymphocytic choriomeningitis virus clone 13 (LCMV-clone13) whereas wild-type (WT) mice do not. Post-infection, PEP-R619W DCs exhibit reduced infection, increased CD86, and decreased PD-L1 expression, both in-vivo and ex-vivo. Transcriptome analysis reveals distinct gene expression in PEP-R619W DCs, with upregulated Jak3 expression. Our finding suggests that PEP-R619W enhances IFN-I signaling as observed by increased pSTAT1 expression and elevated expression of Interferon stimulated genes in DCs. However, PEP-R619W CD8 T cells demonstrate reduced IFN-I signaling, which may contribute to decreased exhaustion. Consistently, PEP-R619W CD8 T cells exhibit more IFNγ and Granzyme B production, specifically in response to the minor epitope of LCMV-cl13 (gp276-284). These findings highlight PEP-R619W as a modulator of IFN-I signaling, preventing immune dysfunction and promoting viral clearance through cell-type-specific effects, offering a potential therapeutic approach for chronic infections.