TY - JOUR
T1 - Endogenous self-peptides guard immune privilege of the central nervous system
AU - Kim, Min Woo
AU - Gao, Wenqing
AU - Lichti, Cheryl F.
AU - Gu, Xingxing
AU - Dykstra, Taitea
AU - Cao, Jay
AU - Smirnov, Igor
AU - Boskovic, Pavle
AU - Kleverov, Denis
AU - Salvador, Andrea F.M.
AU - Drieu, Antoine
AU - Kim, Kyungdeok
AU - Blackburn, Susan
AU - Crewe, Clair
AU - Artyomov, Maxim N.
AU - Unanue, Emil R.
AU - Kipnis, Jonathan
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2025/1/2
Y1 - 2025/1/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85211056981&partnerID=8YFLogxK
U2 - 10.1038/s41586-024-08279-y
DO - 10.1038/s41586-024-08279-y
M3 - Article
C2 - 39476864
AN - SCOPUS:85211056981
SN - 0028-0836
VL - 637
SP - 176
EP - 183
JO - Nature
JF - Nature
IS - 8044
ER -