RESUMO
During influenza A virus (IAV) infection, changes in the lung's physical and immunological defenses predispose the host to bacterial superinfections. Invariant natural killer T (iNKT) cells are innate-like T lymphocytes that have beneficial or harmful functions during infection. We investigated the iNKT cells' role in a model of invasive pneumococcal superinfection. The use of Jα18-/- mice indicated that iNKT cells limited susceptibility to influenza-pneumococcal infection and reduced the lethal synergism. This role did not depend on immune-based anti-bacterial mechanisms. At the time of bacterial exposure, iNKT cells from IAV-experienced mice failed to produce antipneumococcal interferon-γ and adoptive transfer of fresh iNKT cells before Streptococcus pneumoniae challenge did not restore anti-bacterial host defenses. Impaired iNKT cell activation in superinfected animals was related to the IAV-induced immunosuppressive cytokine interleukin-10 (IL-10), rather than to an intrinsic functional defect. IL-10 dampened the activation of iNKT cells in response to pneumococci by inhibiting the production of IL-12 by pulmonary monocyte-derived dendritic cells. Neutralization of IL-10 restored iNKT cell activation and tends to increase resistance to secondary bacterial infection. Overall, iNKT cells have a beneficial role (upstream of bacterial colonization) in controlling influenza-pneumococcal superinfection, although they represent novel targets of immunosuppression at the time of bacterial challenge.
Assuntos
Vírus da Influenza A/imunologia , Interleucina-10/metabolismo , Pulmão/imunologia , Células T Matadoras Naturais/imunologia , Infecções por Orthomyxoviridae/imunologia , Infecções Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Animais , Anticorpos Neutralizantes/metabolismo , Células Cultivadas , Células Dendríticas/imunologia , Suscetibilidade a Doenças , Tolerância Imunológica , Imunidade Inata , Interleucina-10/imunologia , Interleucina-12/metabolismo , Pulmão/microbiologia , Pulmão/virologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T alfa-beta/genética , SuperinfecçãoRESUMO
IL-10 is one of the key cytokines preventing inflammation-mediated tissue damage. In an attempt to identify IL-10-producing cells in vivo, several groups have recently developed IL-10 reporter mouse strains. Up until now, in total, eight IL-10 reporter strains have been published. This incomparable interest in IL-10 reporter mice emphasizes the importance and difficulties in tracking and subsequently investigating the role of IL-10-producing cells in infectious, inflammatory, autoimmune and cancer diseases. In this review, I summarize and compare the properties of those published IL-10 reporter mouse models. I also discuss the necessity to develop new strategies to generate 'multi-cytokine' reporter mouse models enabling highly sensitive in/ex vivo detection of many cytokines in the same single cell. Such 'multi-cytokine' reporter mice will enable to reconsider the dichotomy 'T-effector versus T-regulatory' paradigm and to provide an accurate revised model for cellular sources of cytokines. Finally, I propose to launch cooperative, international initiatives to promote and coordinate the generation of accurate, combinatorial, reporter mice for every individual murine cytokine.