ECM29/Proteasome-Mediated Self-Antigen Generation by CNS-Resident Neuroglia Promotes Regulatory T Cell Activation
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PROVIDER: PRJNA1055460 | ENA |
REPOSITORIES: ENA
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Project description:Proteasomes generate antigenic peptides presented on cell surfaces - a process that in neuroglia is highly responsive to external stimuli. However, the function of the self-antigens presented by CNS parenchymal cells remains unclear. Here, we report that the fidelity of neuroglial self-antigens is crucial to suppress encephalitogenic T cell responses via elevating regulatory T cell (Treg) populations. We demonstrate that loss of the proteasome adaptor protein Ecm29 alters the efficacy and accuracy of antigen generation. Inducible oligodendroglia- or microglia conditional Ecm29 knockout mice exhibit higher susceptibility of experimental autoimmune encephalomyelitis (EAE) than control counterparts, coincident with reduced Tregs populations in spinal cord. Immunopeptidome profiling identifies self-antigens that modulate myelin-reactive T cell responses. Intraspinal AAV/Olig001-mediated expression of the self-antigen NDUFA1p ameliorated EAE and expands NDUFA1p-recognizing CD103+CD8+CD122+ Tregs. Thus, Ecm29/proteasome-controlled, neuroglia-derived self-antigens modulate CNS immune tolerance.
2024-12-06 | GSE251784 | GEO
Project description:The central nervous system (CNS), despite the presence of strategically positioned anatomical barriers designed to protect 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 system. How the CNS retains such responsiveness while maintaining an immunologically unique status remains an outstanding conundrum. In searching for molecular cues that derive from the CNS and allow its direct communication with the immune system, we discovered a repertoire of CNS-derived endogenous regulatory self-peptides presented on major histocompatibility complex (MHC) II molecules at the CNS borders. During homeostasis, a preponderance of 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. With neuroinflammatory disease, however, the presentation of regulatory self-peptides diminished. Upon boosting the presentation of these regulatory self-peptides, a population of suppressor CD4+ T cells could be expanded, controlling CNS autoimmunity in a CTLA-4 and TGF dependent manner. This unexpected discovery of CNS-derived autoimmune self-peptides may be the molecular key adapting the CNS to maintain continuous dialogue with the immune system while balancing overt autoreactivity. This sheds new light on how we conceptually think about and therapeutically target neuroinflammatory and neurodegenerative diseases.
2024-10-11 | GSE272901 | GEO
Project description:In this work we report that early developing B cells present in the meninges of mice at all ages. Single cell RNA-sequencing (scRNA-seq) analysis revealed a consecutive trajectory of meningeal developing B cells in mice and non-human primates (NHPs). Parabiosis together with lineage tracing of hematopoietic stem cells (HSCs) showed that meningeal developing B cells are continuously replenished from the HSC-derived progenitors via a circulation-independent route. Importantly, autoreactive immature B cells which recognize myelin oligodendrocyte glycoprotein (MOG), a central nervous system (CNS)-specific antigen, are eliminated from the meninges but not BM. Furthermore, genetic deletion of MOG tolerated the development/presence/residence of self-reactive B cells in the meninges. Thus, we propose that meninges function as a unique reservoir for B cell development, allowing in situ negative selection of CNS-antigen-autoreactive B cell clones to ensure a local non-self-reactive immune repertoire.
2021-11-01 | GSE176263 | GEO
Project description:Endogenous self-peptides guard CNS immune privilege
| PRJNA1139207 | ENA
Project description:The central nervous system (CNS), despite the presence of strategically positioned anatomical barriers designed to protect 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 system. How the CNS retains such responsiveness while maintaining an immunologically unique status remains an outstanding conundrum. In searching for molecular cues that derive from the CNS and allow its direct communication with the immune system, we discovered a repertoire of CNS-derived endogenous regulatory self-peptides presented on major histocompatibility complex (MHC) II molecules at the CNS borders. During homeostasis, a preponderance of 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. With neuroinflammatory disease, however, the presentation of regulatory self-peptides diminished. Upon boosting the presentation of these regulatory self-peptides, a population of suppressor CD4+ T cells could be expanded, controlling CNS autoimmunity in a CTLA-4 and TGF dependent manner. This unexpected discovery of CNS-derived autoimmune self-peptides may be the molecular key adapting the CNS to maintain continuous dialogue with the immune system while balancing overt autoreactivity. This sheds new light on how we conceptually think about and therapeutically target neuroinflammatory and neurodegenerative diseases.
2024-10-11 | GSE276987 | GEO
Project description:The central nervous system (CNS), despite the presence of strategically positioned anatomical barriers designed to protect 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 system. How the CNS retains such responsiveness while maintaining an immunologically unique status remains an outstanding conundrum. In searching for molecular cues that derive from the CNS and allow its direct communication with the immune system, we discovered a repertoire of CNS-derived endogenous regulatory self-peptides presented on major histocompatibility complex (MHC) II molecules at the CNS borders. During homeostasis, a preponderance of 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. With neuroinflammatory disease, however, the presentation of regulatory self-peptides diminished. Upon boosting the presentation of these regulatory self-peptides, a population of suppressor CD4+ T cells could be expanded, controlling CNS autoimmunity in a CTLA-4 and TGF dependent manner. This unexpected discovery of CNS-derived autoimmune self-peptides may be the molecular key adapting the CNS to maintain continuous dialogue with the immune system while balancing overt autoreactivity. This sheds new light on how we conceptually think about and therapeutically target neuroinflammatory and neurodegenerative diseases.
2024-10-11 | GSE273051 | GEO
Project description:In chronic inflammatory diseases of the central nervous system (CNS), immune cells persisting behind the blood-brain barrier are supposed to promulgate local tissue destruction. The drivers of such compartmentalized inflammation remain unclear, but tissue-resident memory T cells (TRM) represent a potentially important cellular player in this process
2022-02-19 | E-MTAB-11422 | biostudies-arrayexpress
Project description:In chronic inflammatory diseases of the central nervous system (CNS), immune cells persisting behind the blood-brain barrier are supposed to promulgate local tissue destruction. The drivers of such compartmentalized inflammation remain unclear, but tissue-resident memory T cells (TRM) represent a potentially important cellular player in this process
2022-03-14 | E-MTAB-11511 | biostudies-arrayexpress
Project description:Endogenous self-peptides guard CNS immune privilege [TCR_Dura-dCLN]
| PRJNA1139844 | ENA
Project description:Endogenous self-peptides guard CNS immune privilege [TCR-seq]
| PRJNA1159893 | ENA