Targeting Talin1 to reprogram dendritic cell activation landscapes: A mechanistically grounded cell therapy for multiple sclerosis model.

Abstract

This study investigated the role of Talin1 in regulating dendritic cell (DC) activation and the neuroprotective benefits of Talin1-knockdown DCs in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Bone marrow-derived DCs (BMDCs) were transduced with shTalin1 lentiviral vectors in vitro. Their morphological and biochemical profiles, surface molecules expression, cytokines production, capacity to induce T cell responses, as well as regulatory mechanisms, were comprehensively assessed. In vivo, Talin1-knockdown BMDCs loaded with the MOG_35-55 peptide were administered preclinically and therapeutically to EAE mice, with subsequent evaluation of EAE development, inflammatory infiltration, demyelination, and Th/Treg responses. Results demonstrated that Talin1 knockdown significantly inhibited the activation of BMDCs, as evidenced by decreased expression of surface molecules (MHCII, CD80, CD86) and pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), increased expression of anti-inflammatory cytokine (IL-10), differential morphology, ultrastructure, and biochemical characteristics, accompanied by limited ability to stimulate CD4+T cell proliferation and polarization toward Th1 and Th17 subsets. Moreover, RNA-sequencing revealed downregulation of immune/inflammation-related processes and pathways in Talin1-knockdown BMDCs. Mechanistically, inhibition of the TLR4/MyD88/NF-κB pathway in BMDCs contributed to these effects. In vivo, Talin1-knockdown BMDCs significantly delayed the pathogenesis & progression of EAE, alleviated their neurological deficits and pathology, decreased Th1 and Th17 lineage levels, and boosted the abundance of Treg cells. Collectively, these findings indicate that Talin1 orchestrates BMDCs activation, and Talin1-knockdown BMDCs protect against EAE by rebalancing Th1/Th17/Treg dynamics, suggesting a potential approach for the development of precision therapies for MS and other autoimmune disorders.