Hypoxia enhances CD8+ TC2 cell-dependent airway hyperresponsiveness and inflammation through hypoxia-inducible factor 1α.
J Allergy Clin Immunol
; 143(6): 2026-2037.e7, 2019 06.
Article
em En
| MEDLINE
| ID: mdl-30660639
ABSTRACT
BACKGROUND:
CD8+ type 2 cytotoxic T (TC2) cells undergo transcriptional reprogramming to IL-13 production in the presence of IL-4 to become potent, steroid-insensitive, pathogenic effector cells in asthmatic patients and in mice in a model of experimental asthma. However, no studies have described the effects of hypoxia exposure on TC2 cell differentiation.OBJECTIVE:
We determined the effects of hypoxia exposure on IL-13-producing CD8+ TC2 cells.METHODS:
CD8+ transgenic OT-1 cells differentiated with IL-2 and IL-4 (TC2 cells) were exposed to normoxia (21% oxygen) or hypoxia (3% oxygen), and IL-13 production in vitro was monitored. After differentiation under these conditions, cells were adoptively transferred into CD8-deficient mice, and lung allergic responses, including airway hyperresponsiveness to inhaled methacholine, were assessed. The effects of pharmacologic inhibitors of hypoxia-inducible factor (HIF) 1α and HIF-2α were determined, as were responses in HIF-1α-deficient OT-1 cells.RESULTS:
Under hypoxic conditioning, CD8+ TC2 cell differentiation was significantly enhanced, with increased numbers of IL-13+ T cells and increased production of IL-13 in vitro. Adoptive transfer of TC2 cells differentiated under hypoxic conditioning restored lung allergic responses in sensitized and challenged CD8-deficient recipients to a greater degree than seen in recipients of TC2 cells differentiated under normoxic conditioning. Pharmacologic inhibition of HIF-1α or genetic manipulation to reduce HIF-1α expression reduced the hypoxia-enhanced differentiation of TC2 cells, IL-13 production, and the capacity of transferred cells to restore lung allergic responses in vivo. IL-4-dependent, hypoxia-mediated increases in HIF-1α and TC2 cell differentiation were shown to be mediated through activation of Janus kinase 1/3 and GATA-3.CONCLUSIONS:
Hypoxia enhances CD8+ TC2 cell-dependent airway hyperresponsiveness and inflammation through HIF-1α activation. These findings coupled with the known insensitivity of CD8+ T cells to corticosteroids suggests that activation of the IL-4-HIF-1α-IL-13 axis might play a role in the development of steroid-refractory asthma.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Hipersensibilidade Respiratória
/
Linfócitos T CD8-Positivos
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Subunidade alfa do Fator 1 Induzível por Hipóxia
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Inflamação
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Hipóxia
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article