Identification of the endogenous self-peptides presented by MHC-Ⅰa and Qa-1 molecules on activated T cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus Musculus
SUBMITTER: 
Linrong Lu
PROVIDER: PXD055454 | iProX | Sat Aug 31 00:00:00 BST 2024
REPOSITORIES: iProX
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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.
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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.
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Project description:CD4+ T lymphocytes play a major role in the establishment and maintenance of immunity. They are activated by antigenic peptides derived from extracellular or newly synthesized (endogenous) proteins presented on the surface of antigen presenting cells (APCs) by the MHC-II molecules. The pathways leading to endogenous MHC-II presentation remain poorly characterized. We demonstrate here that the autophagy receptor, T6BP, influences both autophagy-dependent and -independent endogenous presentation of HIV- and HCMV-derived peptides. By studying the immunopeptidome of MHC-II molecules, we show that T6BP affects both the quantity and quality of peptides presented. T6BP silencing induces mislocalization of the MHC-II-loading compartments and a rapid degradation of the invariant chain (CD74) without altering the expression and internalization kinetics of MHC-II molecules. T6BP also controls the ER localization of the chaperone calnexin that we identified as a T6BP partner. Remarkably, calnexin silencing in APCs replicates the functional consequences of T6BP silencing: decreased CD4+ T cell activation and exacerbated CD74 degradation. Altogether, we unravel T6BP as a key player of the MHC-II-restricted endogenous presentation pathway and we propose one potential mechanism of action.
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Project description:CD4+ T lymphocytes play a major role in the establishment and maintenance of immunity. They are activated by antigenic peptides derived from extracellular or newly synthesized (endogenous) proteins presented on the surface of antigen presenting cells (APCs) by the MHC-II molecules. The pathways leading to endogenous MHC-II presentation remain poorly characterized. We demonstrate here that the autophagy receptor, T6BP, influences both autophagy-dependent and -independent endogenous presentation of HIV- and HCMV-derived peptides. By studying the immunopeptidome of MHC-II molecules, we show that T6BP affects both the quantity and quality of peptides presented. T6BP silencing induces mislocalization of the MHC-II-loading compartments and a rapid degradation of the invariant chain (CD74) without altering the expression and internalization kinetics of MHC-II molecules. T6BP also controls the ER localization of the chaperone calnexin that we identified as a T6BP partner. Remarkably, calnexin silencing in APCs replicates the functional consequences of T6BP silencing: decreased CD4+ T cell activation and exacerbated CD74 degradation. Altogether, we unravel T6BP as a key player of the MHC-II-restricted endogenous presentation pathway and we propose one potential mechanism of action.
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