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

## TL;DR

MyD88 deficiency in mice reduces autoimmune inflammation by affecting dendritic cells and T cells, offering a potential treatment target for multiple sclerosis.

## Contribution

The study reveals MyD88's dual role in dendritic cells and T cells during autoimmune neuroinflammation.

## Key findings

- MyD88 deficiency impairs dendritic cell maturation and cytokine production.
- MyD88 deficiency reduces Th1 and Th17 cell differentiation and T cell activation.
- MyD88 is highly expressed in dendritic cells and CD4+ T cells in multiple sclerosis patients.

## 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 CD4+ T 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, MyD88−/− DCs 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.

This study investigates the role of MyD88 in dendritic cells (DCs) and T cells during experimental autoimmune encephalomyelitis (EAE). We found that MyD88 is highly expressed in DCs and CD4+ T cells in people with multiple sclerosis, and its deficiency impairs DC maturation, reduces pro‐inflammatory cytokine production, weakens DC–T cell interactions, and limits Th1/Th17 differentiation, highlighting its critical role in driving autoimmune neuroinflammation and its potential as a therapeutic target.