Endogenous self-peptides guard immune privilege of the central nervous system

Min Woo Kim, Wenqing Gao, Cheryl F. Lichti, Xingxing Gu, Taitea Dykstra, Jay Cao, Igor Smirnov, Pavle Boskovic, Denis Kleverov, Andrea F. M. Salvador, Antoine Drieu, Kyungdeok Kim, Susan Blackburn, Clair Crewe, Maxim N. Artyomov, Emil R. Unanue and Jonathan Kipnis ()
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Min Woo Kim: Washington University in St Louis
Wenqing Gao: Washington University in St Louis
Cheryl F. Lichti: Washington University in St Louis
Xingxing Gu: Washington University in St Louis
Taitea Dykstra: Washington University in St Louis
Jay Cao: Washington University in St Louis
Igor Smirnov: Washington University in St Louis
Pavle Boskovic: Washington University in St Louis
Denis Kleverov: Washington University in St Louis
Andrea F. M. Salvador: Washington University in St Louis
Antoine Drieu: Washington University in St Louis
Kyungdeok Kim: Washington University in St Louis
Susan Blackburn: Washington University in St Louis
Clair Crewe: Washington University in St Louis
Maxim N. Artyomov: Washington University in St Louis
Emil R. Unanue: Washington University in St Louis
Jonathan Kipnis: Washington University in St Louis

Nature, 2025, vol. 637, issue 8044, 176-183

Abstract: Abstract Despite the presence of strategically positioned anatomical barriers designed to protect the central nervous system (CNS), it is not entirely isolated from the immune system1,2. 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 question. Here, in searching for molecular cues that derive from the CNS and enable its direct communication with the immune system, we identified an endogenous repertoire of CNS-derived regulatory self-peptides presented on major histocompatibility complex class II (MHC-II) molecules in the CNS and at its 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. However, in neuroinflammatory disease, the presentation of regulatory self-peptides diminished. After 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. CNS-derived regulatory self-peptides may be the molecular key to ensuring a continuous dialogue between the CNS and the immune system while balancing overt autoreactivity. This sheds light on how we conceptually think about and therapeutically target neuroinflammatory and neurodegenerative diseases.

Date: 2025
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DOI: 10.1038/s41586-024-08279-y

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