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1.
Nat Immunol ; 17(6): 656-65, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27043409

RESUMO

Group 2 innate lymphoid cells (ILC2s) regulate tissue inflammation and repair after activation by cell-extrinsic factors such as host-derived cytokines. However, the cell-intrinsic metabolic pathways that control ILC2 function are undefined. Here we demonstrate that expression of the enzyme arginase-1 (Arg1) during acute or chronic lung inflammation is a conserved trait of mouse and human ILC2s. Deletion of mouse ILC-intrinsic Arg1 abrogated type 2 lung inflammation by restraining ILC2 proliferation and dampening cytokine production. Mechanistically, inhibition of Arg1 enzymatic activity disrupted multiple components of ILC2 metabolic programming by altering arginine catabolism, impairing polyamine biosynthesis and reducing aerobic glycolysis. These data identify Arg1 as a key regulator of ILC2 bioenergetics that controls proliferative capacity and proinflammatory functions promoting type 2 inflammation.


Assuntos
Arginase/metabolismo , Linfócitos/fisiologia , Pneumonia/imunologia , Animais , Arginase/genética , Proliferação de Células/genética , Células Cultivadas , Citocinas/metabolismo , Glicólise/genética , Humanos , Imunidade Inata , Ativação Linfocitária/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Poliaminas/metabolismo , Células Th2/imunologia
2.
Immunity ; 50(2): 505-519.e4, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30770247

RESUMO

Innate lymphoid cells (ILC) play critical roles in regulating immunity, inflammation, and tissue homeostasis in mice. However, limited access to non-diseased human tissues has hindered efforts to profile anatomically-distinct ILCs in humans. Through flow cytometric and transcriptional analyses of lymphoid, mucosal, and metabolic tissues from previously healthy human organ donors, here we have provided a map of human ILC heterogeneity across multiple anatomical sites. In contrast to mice, human ILCs are less strictly compartmentalized and tissue localization selectively impacts ILC distribution in a subset-dependent manner. Tissue-specific distinctions are particularly apparent for ILC1 populations, whose distribution was markedly altered in obesity or aging. Furthermore, the degree of ILC1 population heterogeneity differed substantially in lymphoid versus mucosal sites. Together, these analyses comprise a comprehensive characterization of the spatial and temporal dynamics regulating the anatomical distribution, subset heterogeneity, and functional potential of ILCs in non-diseased human tissues.


Assuntos
Imunidade Inata/imunologia , Linfócitos/imunologia , Especificidade de Órgãos/imunologia , Transcriptoma/imunologia , Adolescente , Adulto , Idoso , Envelhecimento/genética , Animais , Criança , Pré-Escolar , Feminino , Heterogeneidade Genética , Humanos , Imunidade Inata/genética , Lactente , Recém-Nascido , Linfócitos/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Especificidade de Órgãos/genética , Transcriptoma/genética , Adulto Jovem
3.
Science ; 359(6379): 1056-1061, 2018 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-29496881

RESUMO

The type 2 inflammatory response is induced by various environmental and infectious stimuli. Although recent studies identified group 2 innate lymphoid cells (ILC2s) as potent sources of type 2 cytokines, the molecular pathways controlling ILC2 responses are incompletely defined. Here we demonstrate that murine ILC2s express the ß2-adrenergic receptor (ß2AR) and colocalize with adrenergic neurons in the intestine. ß2AR deficiency resulted in exaggerated ILC2 responses and type 2 inflammation in intestinal and lung tissues. Conversely, ß2AR agonist treatment was associated with impaired ILC2 responses and reduced inflammation in vivo. Mechanistically, we demonstrate that the ß2AR pathway is a cell-intrinsic negative regulator of ILC2 responses through inhibition of cell proliferation and effector function. Collectively, these data provide the first evidence of a neuronal-derived regulatory circuit that limits ILC2-dependent type 2 inflammation.


Assuntos
Imunidade Adaptativa , Neurônios Adrenérgicos/imunologia , Imunidade Inata , Linfócitos/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Animais , Humanos , Inflamação/imunologia , Intestinos/imunologia , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Rede Nervosa/imunologia , Receptores Adrenérgicos beta 2/genética , Transdução de Sinais
4.
Nat Rev Immunol ; 14(1): 24-35, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24336101

RESUMO

Memory T cells constitute the most abundant lymphocyte population in the body for the majority of a person's lifetime; however, our understanding of memory T cell generation, function and maintenance mainly derives from mouse studies, which cannot recapitulate the exposure to multiple pathogens that occurs over many decades in humans. In this Review, we discuss studies focused on human memory T cells that reveal key properties of these cells, including subset heterogeneity and diverse tissue residence in multiple mucosal and lymphoid tissue sites. We also review how the function and the adaptability of human memory T cells depend on spatial and temporal compartmentalization.


Assuntos
Memória Imunológica , Subpopulações de Linfócitos T/imunologia , Imunidade Adaptativa , Animais , Antígenos , Reações Cruzadas , Homeostase , Humanos , Imunidade nas Mucosas , Tecido Linfoide/imunologia , Camundongos , Microbiota/imunologia , Modelos Imunológicos , Vacinas/imunologia
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