RESUMO
Group 2 innate lymphoid cells (ILC2s) orchestrate protective type 2 immunity and have been implicated in various immune disorders. In the mouse, circulatory inflammatory ILC2s (iILC2s) were identified as a major source of type 2 cytokines. The human equivalent of the iILC2 subset remains unknown. Here, we identify a human inflammatory ILC2 population that resides in inflamed mucosal tissue and is specifically marked by surface CD45RO expression. CD45RO+ ILC2s are derived from resting CD45RA+ ILC2s upon activation by epithelial alarmins such as IL-33 and TSLP, which is tightly linked to STAT5 activation and up-regulation of the IRF4/BATF transcription factors. Transcriptome analysis reveals marked similarities between human CD45RO+ ILC2s and mouse iILC2s. Frequencies of CD45RO+ inflammatory ILC2 are increased in inflamed mucosal tissue and in the circulation of patients with chronic rhinosinusitis or asthma, correlating with disease severity and resistance to corticosteroid therapy. CD45RA-to-CD45RO ILC2 conversion is suppressed by corticosteroids via induction of differentiation toward an immunomodulatory ILC2 phenotype characterized by low type 2 cytokine and high amphiregulin expression. Once converted, however, CD45RO+ ILC2s are resistant to corticosteroids, which is associated with metabolic reprogramming resulting in the activation of detoxification pathways. Our combined data identify CD45RO+ inflammatory ILC2s as a human analog of mouse iILC2s linked to severe type 2 inflammatory disease and therapy resistance.
Assuntos
Asma/tratamento farmacológico , Glucocorticoides/farmacologia , Antígenos Comuns de Leucócito/metabolismo , Linfócitos/imunologia , Pólipos Nasais/tratamento farmacológico , Adolescente , Adulto , Idoso , Asma/diagnóstico , Asma/imunologia , Resistência a Medicamentos/imunologia , Feminino , Glucocorticoides/uso terapêutico , Humanos , Imunidade Inata , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Pólipos Nasais/imunologia , Índice de Gravidade de Doença , Adulto JovemRESUMO
Human ILCs are classically categorized into five subsets; cytotoxic CD127- CD94+ NK cells and non-cytotoxic CD127+ CD94- , ILC1s, ILC2s, ILC3s, and LTi cells. Here, we identify a previously unrecognized subset within the CD127+ ILC population, characterized by the expression of the cytotoxic marker CD94. These CD94+ ILCs resemble conventional ILC3s in terms of phenotype, transcriptome, and cytokine production, but are highly cytotoxic. IL-15 was unable to induce differentiation of CD94+ ILCs toward mature NK cells. Instead, CD94+ ILCs retained RORγt, CD127 and CD200R1 expression and produced IL-22 in response to IL-15. Culturing non-cytotoxic ILC3s with IL-12 induced upregulation of CD94 and cytotoxic activity, effects that were not observed with IL-15 stimulation. Thus, human helper ILCs can acquire a cytotoxic program without differentiating into NK cells.
Assuntos
Diferenciação Celular/imunologia , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/imunologia , Células Matadoras Naturais/imunologia , Linfócitos/imunologia , Animais , Diferenciação Celular/genética , Linhagem Celular , Citotoxicidade Imunológica/genética , Citotoxicidade Imunológica/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imunidade Inata/imunologia , Interleucina-15/farmacologia , Subunidade alfa de Receptor de Interleucina-7/genética , Subunidade alfa de Receptor de Interleucina-7/imunologia , Células Matadoras Naturais/citologia , Células Matadoras Naturais/metabolismo , Linfócitos/citologia , Linfócitos/metabolismo , Camundongos , Subfamília D de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília D de Receptores Semelhantes a Lectina de Células NK/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologiaRESUMO
Recently, human ILCs that express CD117 and CD127 but lack CRTH2 and NKp44 have been shown to contain precursors of ILC1, ILC2, and ILC3. However, these ILCs have not been extensively characterized. We performed an unbiased hierarchical stochastic neighbor embedding (HSNE) analysis of the phenotype of peripheral blood CD117+ ILCs, which revealed the presence of three major subsets: the first expressed NKp46, the second expressed both NKp46 and CD56, and the third expressed KLRG1, but not NKp46 or CD56. Analysis of their cytokine production profiles and transcriptome revealed that NKp46+ ILCs predominantly develop into ILC3s; some of them can differentiate into ILC1/NK-like cells, but they are unable to develop into ILC2s. In contrast, KLRG1+ ILCs predominantly differentiate into ILC2s. Single-cell cultures demonstrate that KLRG1+ ILCs can also differentiate into other ILC subsets depending on the signals they receive. Epigenetic profiling of KLRG1+ ILCs is consistent with the broad differentiation potential of these cells.
Assuntos
Diferenciação Celular/imunologia , Células Matadoras Naturais/metabolismo , Lectinas Tipo C/metabolismo , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Animais , Doadores de Sangue , Linhagem Celular , Citocinas/metabolismo , Epigênese Genética , Humanos , Imunidade Inata , Células Matadoras Naturais/imunologia , Camundongos , Receptor 2 Desencadeador da Citotoxicidade Natural/metabolismo , Tonsila Palatina/patologia , Fenótipo , TranscriptomaRESUMO
Innate lymphoid cells (ILCs) are crucial for the immune surveillance at mucosal sites. ILCs coordinate early eradication of pathogens and contribute to tissue healing and remodeling, features that are dysfunctional in patients with cystic fibrosis (CF). The mechanisms by which ILCs contribute to CF-immunopathology are ill-defined. Here, we show that group 2 ILCs (ILC2s) transdifferentiated into IL-17-secreting cells in the presence of the epithelial-derived cytokines IL-1ß, IL-23 and TGF-ß. This conversion is abrogated by IL-4 or vitamin D3. IL-17 producing ILC2s induce IL-8 secretion by epithelial cells and their presence in nasal polyps of CF patients is associated with neutrophilia. Our data suggest that ILC2s undergo transdifferentiation in CF nasal polyps in response to local cytokines, which are induced by infectious agents.
