RESUMO
Natural killer (NK) cells are traditionally considered as innate cells, but recent studies suggest that NK cells can distinguish antigens, and that memory NK cells expand and protect against viral pathogens. Limited information is available about the mechanisms involved in memory-like NK cell expansion, and their role in bacterial infections and vaccine-induced protective immune responses. In the current study, using a mouse model of tuberculosis (TB) infection, we found that interferon-gamma producing CD3-NKp46+CD27+KLRG1+ memory-like NK cells develop during Bacille Calmette-Guérin vaccination, expand, and provide protection against challenge with Mycobacterium tuberculosis (M. tb). Using antibodies, short interfering RNA and gene-deleted mice, we found that expansion of memory-like NK cells depends on interleukin 21 (IL-21). NKp46+CD27+KLRG1+ NK cells expanded in healthy individuals with latent TB infection in an IL-21-dependent manner. Our study provides first evidence that memory-like NK cells survive long term, expansion depends on IL-21, and involved in vaccine-induced protective immunity against a bacterial pathogen.
Assuntos
Interleucinas/metabolismo , Células Matadoras Naturais/imunologia , Tuberculose Latente/imunologia , Mycobacterium bovis/imunologia , Mycobacterium tuberculosis/imunologia , Adolescente , Adulto , Idoso , Animais , Anticorpos Bloqueadores/metabolismo , Proliferação de Células , Modelos Animais de Doenças , Feminino , Humanos , Imunidade Inata , Memória Imunológica , Interleucinas/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , RNA Interferente Pequeno/genética , Vacinação , Adulto JovemRESUMO
We studied the effect of T cells on IL-18 production by human monocytes in response to Mycobacterium tuberculosis. Addition of activated T cells markedly enhanced IL-18 production by monocytes exposed to M. tuberculosis. This effect was mediated by a soluble factor and did not require cell-to-cell contact. The effect of activated T cells was mimicked by recombinant IFN-gamma and was abrogated by neutralizing Abs to IFN-gamma. IFN-gamma also enhanced the capacity of alveolar macrophages to produce IL-18 in response to M. tuberculosis, suggesting that this mechanism also operates in the lung during mycobacterial infection. IFN-gamma increased IL-18 production by increasing cleavage of pro-IL-18 to mature IL-18, as it enhanced caspase-1 activity but did not increase IL-18 mRNA expression. These findings suggest that activated T cells can contribute to the initial immune response by augmenting IL-18 production by monocytes in response to an intracellular pathogen.
Assuntos
Interleucina-18/biossíntese , Líquido Intracelular/imunologia , Líquido Intracelular/microbiologia , Monócitos/metabolismo , Monócitos/microbiologia , Mycobacterium tuberculosis/imunologia , Linfócitos T/imunologia , Regulação para Cima/imunologia , Caspase 1/fisiologia , Células Cultivadas , Técnicas de Cocultura , Humanos , Interferon gama/farmacologia , Interferon gama/fisiologia , Interleucina-18/genética , Líquido Intracelular/metabolismo , Ativação Linfocitária , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Monócitos/enzimologia , Monócitos/imunologia , Mycobacterium tuberculosis/patogenicidade , Processamento Pós-Transcricional do RNA/imunologia , RNA Mensageiro/biossíntese , Proteínas Recombinantes/farmacologia , Solubilidade , Linfócitos T/metabolismoRESUMO
To evaluate the immunologic factors that contribute to protection against Mycobacterium avium complex (MAC), cytokine production by peripheral blood mononuclear cells (PBMC) from human immunodeficiency virus-negative persons with pulmonary MAC (MAC patients) and healthy control subjects with a delayed hypersensitivity skin test response to M. avium sensitin (MAS-positive control subjects) was measured. In MAC patients, mycobacterium-stimulated PBMC produced higher concentrations of interleukin (IL)-10 but lower concentrations of interferon (IFN)-gamma, IL-12, and tumor necrosis factor (TNF)-alpha, compared with PBMC from MAS-positive control subjects. Immunolabeling for intracellular IL-10 revealed that this cytokine was produced by both monocytes and T cells. Alveolar macrophages produced TNF-alpha and IL-10 in response to MAC, which suggests that these cytokines are produced in the lungs of patients with pulmonary disease caused by this pathogen. Our findings suggest that IFN-gamma, TNF-alpha, and IL-12 contribute to protection against MAC, whereas IL-10 is immunosuppressive.
Assuntos
Citocinas/biossíntese , Imunocompetência , Complexo Mycobacterium avium/imunologia , Infecção por Mycobacterium avium-intracellulare/imunologia , Adulto , Idoso , Feminino , Humanos , Leucócitos Mononucleares/imunologia , Receptores de Lipopolissacarídeos , Ativação Linfocitária/imunologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/imunologiaRESUMO
To investigate the role of interleukin (IL)-18 in human tuberculosis, IL-18 production was evaluated in blood and at the site of disease in patients with tuberculosis. Mycobacterium tuberculosis-stimulated peripheral blood mononuclear cells (PBMC) from tuberculosis patients secreted less IL-18 and interferon-gamma (IFN-gamma) than did PBMC from healthy persons reactive to tuberculin. M. tuberculosis-induced IFN-gamma production was inhibited by anti-IL-18 and enhanced by recombinant IL-18. Alveolar macrophages secreted IL-18 in response to M. tuberculosis, and IL-18 and IFN-gamma concentrations were higher in pleural fluid of patients with tuberculosis than in pleural fluid of patients with nontuberculous diseases. These findings demonstrate that IL-18 production by PBMC correlates with IFN-gamma production and effective immunity to tuberculosis, suggesting that IL-18 contributes to a protective type 1 cytokine response in persons with mycobacterial infection.