Dendritic cells (DCs) are professional APCs that play a crucial role in initiating robust immune responses against invading pathogens while inducing regulatory responses to the body's tissues and commensal microorganisms. A breakdown of DC-mediated immunological tolerance leads to chronic inflammation and autoimmune disorders. However, cell-intrinsic molecular regulators that are critical for programming DCs to a regulatory state rather than to an inflammatory state are not known. In this study, we show that the activation of the TCF4 transcription factor in DCs is critical for controlling the magnitude of inflammatory responses and limiting neuroinflammation. DC-specific deletion of TCF4 in mice increased Th1/Th17 responses and exacerbated experimental autoimmune encephalomyelitis pathology. Mechanistically, loss of TCF4 in DCs led to heightened activation of p38 MAPK and increased levels of proinflammatory cytokines IL-6, IL-23, IL-1β, TNF-α, and IL-12p40. Consistent with these findings, pharmacological blocking of p38 MAPK activation delayed experimental autoimmune encephalomyelitis onset and diminished CNS pathology in TCF4^ΔDC mice. Thus, manipulation of the TCF4 pathway in DCs could provide novel opportunities for regulating chronic inflammation and represents a potential therapeutic approach to control autoimmune neuroinflammation.

树突状细胞 (DC) 是专业的 APC，在启动针对入侵病原体的强大免疫反应以及诱导对身体组织和共生微生物的调节反应方面发挥着至关重要的作用。DC 介导的免疫耐受的破坏导致慢性炎症和自身免疫性疾病。然而，对于将 DC 编程为调节状态而不是炎症状态至关重要的细胞内在分子调节剂尚不清楚。在这项研究中，我们表明 DCs 中 TCF4 转录因子的激活对于控制炎症反应的幅度和限制神经炎症至关重要。小鼠中 TCF4 的 DC 特异性缺失增加了 Th1/Th17 反应并加剧了实验性自身免疫性脑脊髓炎病理学。机械地，DCs 中 TCF4 的缺失导致 p38 MAPK 的激活增强，促炎细胞因子 IL-6、IL-23、IL-1β、TNF-α 和 IL-12p40 的水平升高。与这些发现一致，p38 MAPK 激活的药理学阻断延迟了实验性自身免疫性脑脊髓炎的发作并减少了 TCF4 中的 CNS 病理学^ΔDC小鼠。因此，对 DCs 中 TCF4 通路的操纵可以为调节慢性炎症提供新的机会，并代表了一种控制自身免疫性神经炎症的潜在治疗方法。