Despite the presence of strategically positioned anatomical barriers designed to protect the central nervous system (CNS), it is not entirely isolated from the immune system. In fact, it remains physically connected to, and can be influenced by, the peripheral immune system. 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.
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http://dx.doi.org/10.1038/s41586-024-08279-y | DOI Listing |
Nature
January 2025
Brain Immunology and Glia (BIG) Center, School of Medicine, Washington University in St Louis, St Louis, MO, USA.
Despite the presence of strategically positioned anatomical barriers designed to protect the central nervous system (CNS), it is not entirely isolated from the immune system. In fact, it remains physically connected to, and can be influenced by, the peripheral immune system. How the CNS retains such responsiveness while maintaining an immunologically unique status remains an outstanding question.
View Article and Find Full Text PDFCell Syst
December 2023
Department of Physiology, McGill University, Montreal, QC H3G 0B1, Canada; Department of Microbiology & Immunology, McGill University, Montreal, QC H3A 1A3, Canada; McGill Research Centre on Complex Traits, McGill University, Montreal, QC H3G 0B1, Canada. Electronic address:
The T cell receptor (TCR) determines specificity and affinity for both foreign and self-peptides presented by the major histocompatibility complex (MHC). Although the strength of TCR interactions with self-pMHC impacts T cell function, it has been challenging to identify TCR sequence features that predict T cell fate. To discern patterns distinguishing TCRs from naive CD4 T cells with low versus high self-reactivity, we used data from 42 mice to train a machine learning (ML) algorithm that identifies population-level differences between TCRβ sequence sets.
View Article and Find Full Text PDFJ Clin Invest
January 2024
Department of Cancer Immunology & Virology, Dana Farber Cancer Institute, Boston, Massachusetts, USA.
Although most CD8+ T cells are equipped to kill infected or transformed cells, a subset may regulate immune responses and preserve self-tolerance. Here, we describe a CD8 lineage that is instructed to differentiate into CD8 T regulatory cells (Tregs) by a surprisingly restricted set of T cell receptors (TCRs) that recognize MHC-E (mouse Qa-1) and several dominant self-peptides. Recognition and elimination of pathogenic target cells that express these Qa-1-self-peptide complexes selectively inhibits pathogenic antibody responses without generalized immune suppression.
View Article and Find Full Text PDFInt J Mol Sci
September 2023
Immuno-Oncology Branch, Division of Rare and Refractory Cancer, National Cancer Center, Goyang 10408, Republic of Korea.
The interaction between regulatory T (Treg) cells and self-reactive T cells is a crucial mechanism for maintaining immune tolerance. In this study, we investigated the cross-activation of Treg cells by self-antigens and its impact on self-reactive CD8 T cell responses, with a focus on the P53 signaling pathway. We discovered that major histocompatibility complex (MHC) I-restricted self-peptides not only activated CD8 T cells but also induced the delayed proliferation of Treg cells.
View Article and Find Full Text PDFJ Autoimmun
November 2023
Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, 187-8502, Japan. Electronic address:
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