自肽的敏感化引起了多种免疫学反应，从自身免疫到肿瘤免疫，取决于肽序列；然而，其潜在机制尚不清楚，因此考虑免疫平衡的治疗选择有限。本研究探讨了髓鞘蛋白脂质体（PLP）的两个重叠优势肽段，即PLP136-150和PLP139-151，它们分别引起了单相型和复发型实验性自身免疫性脑脊髓炎（EAE）。单相型EAE小鼠对任何致脑炎的肽段的EAE再诱导表现出高度抵抗病变，而复发型EAE小鼠则容易并持续进展至EAE再诱导。单相型EAE小鼠对复发和重诱导的抵抗力与CD69+CD103+CD4+CD25高表达的特异性抗原富集的强效调节性T细胞（Tregs）的维持有关，这些细胞在中枢神经系统中扩增并具有持续的抑制活性。这种针对组织的强效特异性抗原Tregs的持久性可持续性与PLP136-150的抗原性有关，取决于其相邻残基。也就是说，PLP136-150的相邻残基能够形成重要排列的强氢键，从而确保其与MHC-II结合的稳定性。这些具有组织选择性作用的强效Tregs仅由PLP136-150的敏感化诱导产生，与EAE的发展无关。这些发现表明，要实现最佳疗效，通过操纵肽段的相邻残基，可以通过自我肽逆向免疫接种实现“良性自身免疫”。版权所有2023年Elsevier Ltd.，由Elsevier Ltd.发表的文章。保留所有权利。

Sensitization to self-peptides induces various immunological responses, from autoimmunity to tumor immunity, depending on the peptide sequence; however, the underlying mechanisms remain unclear, and thus, curative therapeutic options considering immunity balance are limited. Herein, two overlapping dominant peptides of myelin proteolipid protein, PLP136-150 and PLP139-151, which induce different forms of experimental autoimmune encephalomyelitis (EAE), monophasic and relapsing EAE, respectively, were investigated. Mice with monophasic EAE exhibited highly resistant to EAE re-induction with any encephalitogenic peptides, whereas mice with relapsing EAE were susceptible, and progressed, to EAE re-induction. This resistance to relapse and re-induction in monophasic EAE mice was associated with the maintenance of potent CD69+CD103+CD4+CD25high regulatory T-cells (Tregs) enriched with antigen specificity, which expanded preferentially in the central nervous system with sustained suppressive activity. This tissue-preferential sustainability of potent antigen-specific Tregs was correlated with the antigenicity of PLP136-150, depending on its flanking residues. That is, the flanking residues of PLP136-150 enable to form pivotally arranged strong hydrogen bonds that secured its binding stability to MHC-class II. These potent Tregs acting tissue-preferentially were induced only by sensitization of PLP136-150, not by its tolerance induction, independent of EAE development. These findings suggest that, for optimal therapy, "benign autoimmunity" can be critically achieved through inverse vaccination with self-peptides by manipulating their flanking residues.Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.