TY - JOUR

T1 - Repeated immunization with ATRA-containing liposomal adjuvant transdifferentiates Th17 cells to a Tr1-like phenotype

AU - Wørzner, Katharina

AU - Zimmermann, Julie

AU - Buhl, Regitze

AU - Desoi, Anna

AU - Christensen, Dennis

AU - Dietrich, Jes

AU - Nguyen, Nina Dieu Nhien Tran

AU - Lindenstrøm, Thomas

AU - Woodworth, Joshua S.

AU - Alhakeem, Reham Sabah

AU - Yu, Steven

AU - Ødum, Niels

AU - Mortensen, Rasmus

AU - Ashouri, Judith F.

AU - Pedersen, Gabriel K.

N1 - Publisher Copyright: © 2024 The Authors

PY - 2024/4

Y1 - 2024/4

N2 - 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.

AB - 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.

KW - All-trans-retinoic acid (ATRA)

KW - CAF16

KW - Experimental encephalomyelitis model (EAE)

KW - IL-17A fate reporter mice

KW - Th17 cells

KW - Therapeutic vaccine

U2 - 10.1016/j.jaut.2024.103174

DO - 10.1016/j.jaut.2024.103174

M3 - Journal article

C2 - 38377868

AN - SCOPUS:85185913022

VL - 144

JO - Journal of Autoimmunity

JF - Journal of Autoimmunity

SN - 0896-8411

M1 - 103174

ER -