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Updated: Feb 27, 2026
A Simple and Efficient Method for Testing Immunomodulatory Agents for Generation of Tolerogenic Dendritic Cells from Human CD14+ Monocytes
Published on: April 11, 2025
A peptide immunomodulator activates MST1 to expand and stabilize murine and human regulatory T cells for immune
Yu Wang1, Xinnan Liu2, Xiaoxue Li3
1Department of Implantology, School and Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai 200072, China.
The expansion and potentiation of regulatory T cells (Treg cells) offer an appealing approach for achieving immune tolerance and controlling overactive immune responses across a range of diseases. Current therapeutic approaches to expanding and improving function of Treg cells have predominantly relied on protein-based biologics, such as recombinant interleukin-2 (IL-2); in contrast, peptide-based interventions that can expand Treg cells with improved functional stability, enhanced specificity, and favorable safety profiles remain underexplored. Here, using a deep learning model, we identified a hexapeptide (DLST-6P) that preferentially expands both human and murine Treg cells while preserving their stability. When tested in multiple autoimmune and inflammatory disorders, including a humanized mouse model of graft-versus-host disease, DLST-6P exhibited therapeutic efficacy both as a monotherapy and in combination with low-dose IL-2. Mechanistically, we found that DLST-6P directly targets and activates mammalian Ste20-like kinase 1 (MST1) by promoting homodimer formation. After activation by DLST-6P treatment, MST1 phosphorylated the master Treg cell transcription factor forkhead box protein P3 (FOXP3) at serine-390. This promoted the association of FOXP3 with the acetyltransferase tat-interacting protein 60, leading to enhanced FOXP3 acetylation and protein stabilization. Simultaneously, we observed that DLST-6P-mediated activation of MST1 alleviated suppressor of cytokine signaling-mediated inhibition of IL-2 signaling in Treg cells, thereby sensitizing the cells to IL-2 stimulation. Together, these findings unveil a dual mechanistic program through which pharmacological activation of MST1 can boost Treg cell expansion and stability and highlight the translational potential of DLST-6P as a peptide-based immunomodulator for treating autoimmune and inflammatory disorders.
The expansion and potentiation of regulatory T cells (Treg cells) offer an appealing approach for achieving immune tolerance and controlling overactive immune responses across a range of diseases. Current therapeutic approaches to expanding and improving function of Treg cells have predominantly relied on protein-based biologics, such as recombinant interleukin-2 (IL-2); in contrast, peptide-based interventions that can expand Treg cells with improved functional stability, enhanced specificity, and favorable safety profiles remain underexplored. Here, using a deep learning model, we identified a hexapeptide (DLST-6P) that preferentially expands both human and murine Treg cells while preserving their stability. When tested in multiple autoimmune and inflammatory disorders, including a humanized mouse model of graft-versus-host disease, DLST-6P exhibited therapeutic efficacy both as a monotherapy and in combination with low-dose IL-2. Mechanistically, we found that DLST-6P directly targets and activates mammalian Ste20-like kinase 1 (MST1) by promoting homodimer formation. After activation by DLST-6P treatment, MST1 phosphorylated the master Treg cell transcription factor forkhead box protein P3 (FOXP3) at serine-390. This promoted the association of FOXP3 with the acetyltransferase tat-interacting protein 60, leading to enhanced FOXP3 acetylation and protein stabilization. Simultaneously, we observed that DLST-6P-mediated activation of MST1 alleviated suppressor of cytokine signaling-mediated inhibition of IL-2 signaling in Treg cells, thereby sensitizing the cells to IL-2 stimulation. Together, these findings unveil a dual mechanistic program through which pharmacological activation of MST1 can boost Treg cell expansion and stability and highlight the translational potential of DLST-6P as a peptide-based immunomodulator for treating autoimmune and inflammatory disorders.
