MyD88 Deficiency Protects Mice From Experimental Autoimmune Encephalomyelitis by Influencing Both Dendritic Cells and T Cells.

Abstract

Dendritic cells (DCs) play a central role in both the development and maintenance of adaptive immunity by their ability to prime and regulate T cell function. These interactions between DCs and T cells are crucial to the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Myeloid differentiation primary response protein 88 (MyD88) signalling is pivotal in the pathogenesis of MS and EAE; however, its specific contributions across various cell types in the context of these conditions remain inadequately understood. In this study, we reanalysed single-cell RNA sequencing data from MS patients and revealed significant upregulation of MYD88 in DCs and CD4T cells isolated from PBMCs of MS patients. Single-cell RNA sequencing analysis revealed that during the peak phase of EAE, Myd88 is highly expressed in moDCs and pDCs compared to cDCs. Notably, the absence of Myd88 in DCs resulted in significantly reduced interactions with T cell clusters. Our in vivo and in vitro results showed that while MyD88 deficiency did not affect lymphocyte production in the thymus, it resulted in impaired Th1 and Th17 cell differentiation and diminished T cell activation. Mechanistically, MyD88DCs exhibited impaired maturation and a reduced production of pro-inflammatory cytokines, such as IL-6, TNF-α, and IL-12, which may be linked to their role in directing Th1 and Th17 cell differentiation. Our findings suggest that MyD88 is essential for the priming of inflammatory T cells and the activation of DCs, and their interactions with T cells, underscoring its role in neuroinflammation. This study highlights the potential therapeutic implications of targeting MyD88 pathways in MS and related disorders.