Split the dendritic-cell decision: Xcr1+ cDC1-targeted TDO2 nanotherapy to expand antigen-specific Tregs

Pulmonary cDC1s split into Xcr1+ (tolerogenic) and Xcr1− (immunogenic) clusters with distinct transcriptional programs (Jirmo et al., 2023). Independently, dendritic cells overexpressing TDO2 acquire a tolerogenic phenotype that raises Tregs and suppresses Th17 in arthritis models (Jia et al., 2024). This project unites the two by building antigen-coupled nanoparticles with ligands or antibodies that preferentially bind Xcr1+ cDC1s, co-delivering PGE2/TDO2 mRNA or small-molecule inducers to push these DCs into a TDO2-high tolerogenic state while presenting disease-relevant antigens. The goal is to selectively educate antigen-specific Tregs in situ, minimizing collateral effects on effector T cells. Compared to existing tolDC therapies, the novelty is cell-state- and subset-specific programming of cDC1s, rather than bulk DC manipulation, with in vivo single-cell readouts to confirm fate and function. This could generalize across tissues (lung, gut, joint) and indications (allergy, autoimmunity), building on the precision highlighted by Li et al. (2020) and the antigen specificity goals of Que & Li (2021).

References:

1. Regulatory T Cells for the Induction of Transplantation Tolerance.. Weitao Que, Xiao‐Kang Li (2021). Advances in Experimental Medicine and Biology.
2. TDO2-overexpressed Dendritic Cells Possess Tolerogenicity and Ameliorate Collagen-induced Arthritis by Modulating the Th17/Regulatory T Cell Balance.. Chengyan Jia, Yueye Wang, Yi Wang, Meng Cheng, Weibo Dong, Wei Wei, Yingjie Zhao, Yan Chang (2024). Journal of Immunology.
3. Single cell RNA sequencing reveals distinct clusters of Irf8-expressing pulmonary conventional dendritic cells. Adan Chari Jirmo, R. Grychtol, Svenja Gaedcke, Bin Liu, S. Destefano, C. Happle, O. Halle, J. T. Monteiro, A. Habener, O. D. Breiholz, D. DeLuca, G. Hansen (2023). Frontiers in Immunology.