Harnessing autoimmunity with dominant self-peptide: Modulating the sustainability of tissue-preferential antigen-specific Tregs by governing the binding stability via peptide flanking residues

Authors

Youwei Lin, National Center of Neurology and Psychiatry
Shun Sakuraba, Institute for Quantum Life Science
Chandirasegaran Massilamany, Immuno-oncology CRISPR Therapeutics
Jayagopala Reddy, University of Nebraska-Lincoln
Yoshimasa Tanaka, Nagasaki University
Sachiko Miyake, Juntendo University School of Medicine
Takashi Yamamura, National Center of Neurology and Psychiatry

Document Type

Article

Date of this Version

7-25-2023

Citation

Journal of Autoimmunity 140 (2023) 103094. https://doi.org/10.1016/j.jaut.2023.103094

Comments

Open access.

Abstract

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 reinduction in monophasic EAE mice was associated with the maintenance of potent CD69⁺CD103⁺CD4⁺CD25^high 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 selfpeptides by manipulating their flanking residues.