Tr1 cell-mediated protection against autoimmune disease by intranasal administration of a fusion protein targeting cDC1 cells

Abstract

ABSTRACTCurative therapies against autoimmune diseases are lacking. Indeed, most of currently available treatments are only targeting symptoms. We have developed a novel strategy for a therapeutic vaccine against autoimmune diseases based on intranasal administration of a fusion protein tolerogen, which consists of a mutant, enzymatically inactive, cholera toxin A1-subunit genetically fused to disease relevant high affinity peptides and a dimer of D-fragments from protein A. The CTA1R7K-MOG/PLP-DD fusion proteins effectively reduced clinical symptoms in the experimental autoimmune encephalitis (EAE)-model of multiple sclerosis (MS). The treatment induced Tr1 cells, in the draining lymph node, which produced IL-10 and suppressed effector CD4+T cell responses. This effect was dependent on IL-27 signalling, since treatment was ineffective in bone marrow chimeras lacking IL-27Rα within their hematopoietic compartment. scRNA-seq of dendritic cells (DC) in draining lymph nodes demonstrated distinct gene transcriptional changes of cDC1, including enhanced lipid metabolic pathways, induced by the tolerogenic fusion protein. Thus, our results with the tolerogenic fusion protein demonstrates the possibility to vaccinate and protect against disease progression by reinstating tolerance in MS and other autoimmune diseases.