The central nervous system (CNS), despite the presence of strategically positioned anatomical barriers designed to protect it, is not entirely isolated from the immune system^1,2. In fact, it remains physically connected to and can be influenced by the peripheral immune system¹. How the CNS retains such responsiveness while maintaining an immunologically unique status remains an outstanding conundrum. In searching for molecular cues that derive from the CNS and allow its direct communication with the immune system, we discovered an endogenous repertoire of CNS-derived regulatory self-peptides presented on major histocompatibility complex (MHC) II molecules at the CNS borders. During homeostasis, these regulatory self-peptides were found to be bound to MHC II molecules throughout the path of lymphatic drainage from the brain to its surrounding meninges and its draining cervical lymph nodes. With neuroinflammatory disease, however, the presentation of regulatory self-peptides diminished. Upon boosting the presentation of these regulatory self-peptides, a population of suppressor CD4⁺ T cells was expanded, controlling CNS autoimmunity in a CTLA-4 and TGFβ dependent manner. This unexpected discovery of CNS-derived autoimmune self-peptides may be the molecular key adapting the CNS to maintain continuous dialogue with the immune system while balancing overt autoreactivity. This sheds new light on how we conceptually think about and therapeutically target neuroinflammatory and neurodegenerative diseases.

中枢神经系统 （CNS） 尽管存在旨在保护它的战略性解剖屏障，但并未完全与免疫系统隔离^1,2。事实上，它与外周免疫系统保持物理连接，并可能受到其影响¹。CNS 如何在保持免疫学独特状态的同时保持这种反应性仍然是一个悬而未决的难题。在寻找源自 CNS 并允许其与免疫系统直接通信的分子线索时，我们发现了 CNS 衍生的调节性自肽的内源性库，这些肽存在于 CNS 边界的主要组织相容性复合体 （MHC） II 分子上。在稳态过程中，发现这些调节性自身肽在从大脑到周围脑膜及其引流颈部淋巴结的整个淋巴引流路径中与 MHC II 分子结合。然而，对于神经炎症性疾病，调节性自身肽的呈现减少。在促进这些调节性自身肽的呈递后，抑制性 CD4⁺ T 细胞群扩增，以 CTLA-4 和 TGFβ 依赖性方式控制 CNS 自身免疫。CNS 衍生的自身免疫自身肽的这一意外发现可能是使 CNS 适应以保持与免疫系统持续对话同时平衡明显的自身反应性的分子关键。这为我们如何从概念上思考和治疗神经炎症和神经退行性疾病提供了新的视角。