Repeated immunization with ATRA-containing liposomal adjuvant transdifferentiates Th17 cells to a Tr1-like phenotype

• Published in: Journal of autoimmunity 2024-04, Vol.144, p.103174-103174, Article 103174
• Main Authors: Wørzner, Katharina, Zimmermann, Julie, Buhl, Regitze, Desoi, Anna, Christensen, Dennis, Dietrich, Jes, Nguyen, Nina Dieu Nhien Tran, Lindenstrøm, Thomas, Woodworth, Joshua S., Alhakeem, Reham Sabah, Yu, Steven, Ødum, Niels, Mortensen, Rasmus, Ashouri, Judith F., Pedersen, Gabriel K.
• Format: Article
• Language: English
• Subjects: All-trans-retinoic acid (ATRA); CAF16; Experimental encephalomyelitis model (EAE); IL-17A fate reporter mice; Th17 cells; Therapeutic vaccine
• ISSN: 0896-8411; 1095-9157
• DOI: 10.1016/j.jaut.2024.103174

In many autoimmune diseases, autoantigen-specific Th17 cells play a pivotal role in disease pathogenesis. Th17 cells can transdifferentiate into other T cell subsets in inflammatory conditions, however, there have been no attempts to target Th17 cell plasticity using vaccines. We investigated if autoantigen-specific Th17 cells could be specifically targeted using a therapeutic vaccine approach, where antigen was formulated in all-trans retinoic acid (ATRA)-containing liposomes, permitting co-delivery of antigen and ATRA to the same target cell. Whilst ATRA was previously found to broadly reduce Th17 responses, we found that antigen formulated in ATRA-containing cationic liposomes only inhibited Th17 cells in an antigen-specific manner and not when combined with an irrelevant antigen. Furthermore, this approach shifted existing Th17 cells away from IL-17A expression and transcriptomic analysis of sorted Th17 lineage cells from IL-17 fate reporter mice revealed a shift of antigen-specific Th17 cells to exTh17 cells, expressing functional markers associated with T cell regulation and tolerance. In the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, vaccination with myelin-specific (MOG) antigen in ATRA-containing liposomes reduced Th17 responses and alleviated disease. This highlights the potential of therapeutic vaccination for changing the phenotype of existing Th17 cells in the context of immune mediated diseases. [Display omitted] •Autoantigen-specific, pathogenic Th17 cells can be targeted by vaccination.•Antigen delivered in ATRA-liposomes targets only autoantigen-specific Th17 cells.•Transcriptomic analysis revealed vaccine-induced conversion of Th17 to Tr1-like cells.•MOG antigen in ATRA liposomes ameliorates EAE disease correlating with reduced Th17 responses.