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1.
Sci Immunol ; 8(90): eadi3974, 2023 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-38064568

RESUMO

Multiple studies have broadened the roles of natural killer (NK) cells functioning as purely innate lymphocytes by demonstrating that they are capable of putative antigen-specific immunological memory against multiple infectious agents including HIV-1 and influenza. However, the mechanisms underlying antigen specificity remain unknown. Here, we demonstrate that antigen-specific human NK cell memory develops upon exposure to both HIV and influenza, unified by a conserved and epitope-specific targetable mechanism largely dependent on the activating CD94/NKG2C receptor and its ligand HLA-E. We validated the permanent acquisition of antigen specificity by individual memory NK cells by single-cell cloning. We identified elevated expression of KLRG1, α4ß7, and NKG2C as biomarkers of antigen-specific NK cell memory through complex immunophenotyping. Last, we uncovered individual HLA-E-restricted peptides that may constitute the dominant NK cell response in HIV-1- and influenza-infected persons in vivo. Our findings clarify the mechanisms contributing to antigen-specific memory NK cell responses and suggest that they could be potentially targeted therapeutically for vaccines or other therapeutic interventions.


Assuntos
Infecções por HIV , Antígenos HLA-E , Influenza Humana , Subfamília C de Receptores Semelhantes a Lectina de Células NK , Humanos , Antígenos de Histocompatibilidade Classe I , Infecções por HIV/metabolismo , Influenza Humana/metabolismo , Células Matadoras Naturais , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo , Antígenos HLA-E/imunologia , Antígenos HLA-E/metabolismo
2.
Immunity ; 47(3): 566-581.e9, 2017 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-28930663

RESUMO

Microglia play a pivotal role in the maintenance of brain homeostasis but lose homeostatic function during neurodegenerative disorders. We identified a specific apolipoprotein E (APOE)-dependent molecular signature in microglia from models of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Alzheimer's disease (AD) and in microglia surrounding neuritic ß-amyloid (Aß)-plaques in the brains of people with AD. The APOE pathway mediated a switch from a homeostatic to a neurodegenerative microglia phenotype after phagocytosis of apoptotic neurons. TREM2 (triggering receptor expressed on myeloid cells 2) induced APOE signaling, and targeting the TREM2-APOE pathway restored the homeostatic signature of microglia in ALS and AD mouse models and prevented neuronal loss in an acute model of neurodegeneration. APOE-mediated neurodegenerative microglia had lost their tolerogenic function. Our work identifies the TREM2-APOE pathway as a major regulator of microglial functional phenotype in neurodegenerative diseases and serves as a novel target that could aid in the restoration of homeostatic microglia.


Assuntos
Apolipoproteínas E/metabolismo , Glicoproteínas de Membrana/metabolismo , Microglia/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Receptores Imunológicos/metabolismo , Transdução de Sinais , Transcriptoma , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Apoptose/genética , Apoptose/imunologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Análise por Conglomerados , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Marcação de Genes , Humanos , Tolerância Imunológica , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microglia/imunologia , Monócitos/imunologia , Monócitos/metabolismo , Doenças Neurodegenerativas/imunologia , Neurônios/metabolismo , Fagocitose/genética , Fagocitose/imunologia , Fenótipo , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Fator de Crescimento Transformador beta/metabolismo
3.
Nat Commun ; 8: 16041, 2017 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-28737175

RESUMO

Although mouse models exist for many immune-based diseases, the clinical translation remains challenging. Most basic and translational studies utilize only a single inbred mouse strain. However, basal and diseased immune states in humans show vast inter-individual variability. Here, focusing on macrophage responses to lipopolysaccharide (LPS), we use the hybrid mouse diversity panel (HMDP) of 83 inbred strains as a surrogate for human natural immune variation. Since conventional bioinformatics fail to analyse a population spectrum, we highlight how gene signatures for LPS responsiveness can be derived based on an Interleukin-12ß and arginase expression ratio. Compared to published signatures, these gene markers are more robust to identify susceptibility or resilience to several macrophage-related disorders in humans, including survival prediction across many tumours. This study highlights natural activation diversity as a disease-relevant dimension in macrophage biology, and suggests the HMDP as a viable tool to increase translatability of mouse data to clinical settings.


Assuntos
Variação Genética , Ativação de Macrófagos/genética , Modelos Animais , Animais , Predisposição Genética para Doença , Humanos , Imunidade Inata/genética , Inflamação , Lipopolissacarídeos , Masculino , Camundongos , Neoplasias/imunologia , Neoplasias/mortalidade , Fenótipo
4.
Nat Immunol ; 16(12): 1228-34, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26523867

RESUMO

The molecular mechanisms that link the sympathetic stress response and inflammation remain obscure. Here we found that the transcription factor Nr4a1 regulated the production of norepinephrine (NE) in macrophages and thereby limited experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Lack of Nr4a1 in myeloid cells led to enhanced NE production, accelerated infiltration of leukocytes into the central nervous system (CNS) and disease exacerbation in vivo. In contrast, myeloid-specific deletion of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, protected mice against EAE. Furthermore, we found that Nr4a1 repressed autocrine NE production in macrophages by recruiting the corepressor CoREST to the Th promoter. Our data reveal a new role for macrophages in neuroinflammation and identify Nr4a1 as a key regulator of catecholamine production by macrophages.


Assuntos
Sistema Nervoso Central/imunologia , Encefalomielite Autoimune Experimental/imunologia , Inflamação/imunologia , Macrófagos/imunologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/imunologia , Sistema Nervoso Simpático/imunologia , Animais , Linhagem Celular , Células Cultivadas , Sistema Nervoso Central/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/metabolismo , Expressão Gênica/imunologia , Humanos , Inflamação/genética , Inflamação/metabolismo , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Confocal , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Células Mieloides/imunologia , Células Mieloides/metabolismo , Norepinefrina/imunologia , Norepinefrina/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Coelhos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sistema Nervoso Simpático/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/imunologia , Tirosina 3-Mono-Oxigenase/metabolismo
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