A Deep Learning-Designed Oligopeptide Potentiates Tregs Against Periodontitis

Aim or purpose: Exploring small-molecule-induced regulatory T cells (Tregs) potentiation to treat chronic periodontitis. Current strategies to increase Tregs mainly focus on protein-based biologics, yet these macromolecules have limitation in treating chronic diseases since their high immunogenicity and unstability effects (Chen, Z., Barbi, J., Bu, S., Yang, H.Y., Li, Z., Gao, Y., Jinasena, D., Fu, J., Lin, F., Chen, C., et al. (2013). The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3. Immunity 39, 272-285.). Materials and methods: Utilizing a modified N-gram model, we identified a hexapeptide, DLST-6P, that amplifies IL-2R-STAT5 signaling. Flow cytometry and western blot assays were employed to observe the effect of DLST-6P on Tregs in vitro. Animal experiments were approved by Clinical Trial Ethics Committee of Affiliated Stomatology Hospital of Tongji University. The periodontitis model induced by silk thread ligation was used to evaluate the efficacy of DLST-6P in treating periodontitis in vivo. IP-MS assay was used to explore the direct target of DLST-6P in Tregs. Results: DLST-6P significantly enhanced Treg proliferation more effectively than IL-2 proteins, alleviating gingival inflammation and promoting periodontal regeneration. Mechanistically, DLST-6P activates MST1 kinase, thereby mitigating SOCS1-mediated inhibition of IL-2R-STAT5 signaling in Tregs. Conclusions: This study identifies DLST-6P as a potent peptide-based immunomodulator for preferential Treg potentiation, offering novel therapeutic opportunities for managing immune dysregulation disorders with enhanced specificity and safety profiles to treat periodontitis.