Costa Paola, Sivori Simona, Bozzano Federica, Martini Isabella, Moretta Alessandro, Moretta Lorenzo, De Maria Andrea
Istituto Giannina Gaslini, Genova, Italy.
Eur J Immunol. 2009 Jan;39(1):147-58. doi: 10.1002/eji.200838532.
Impaired control of chronic pathogen replication may be associated to alterations of NK-cell function. Whether mechanisms underlying this dysfunction involve perturbations of differentiating NK cells is still unknown. We studied an "in vitro" model of differentiation from CD34(+)Lin(-) precursors growing only myelomonocytes and maturing NK cells and where myelomonocytes could be suitably infected with HSV, HIV, or vaccinia. Cultures were evaluated by cytofluorometry and cytotoxicity assays for perturbations in differentiating NK cells. Increased expression of natural cytotoxicity receptors on maturing NK cells with increased cytolytic activity was observed with HSV-1 infection, and with vaccinia while no modulation of NK-cell phenotype nor cytotoxic activity were evident with an ssRNA lentivirus (HIV-1). In the presence of constant IL-12 and IL-15 concentrations, the observed effect did not require cell contact, involved IFN-alpha and was not reproduced by the addition of TLR9 agonist, nor blocked by TLR9 antagonists. Virus replication at sites of NK-cell precursor development may have different outcomes depending on the interaction between invading viruses and maturing NK cells. Thus, NK-cell precursors may be involved in the immune response to dsDNA viruses and possibly contribute to efficient control of virus infection.
慢性病原体复制控制受损可能与自然杀伤细胞（NK细胞）功能改变有关。这种功能障碍的潜在机制是否涉及分化中的NK细胞扰动仍不清楚。我们研究了一种“体外”分化模型，该模型从仅产生髓单核细胞和成熟NK细胞的CD34(+)Lin(-)前体开始，并且髓单核细胞可以被单纯疱疹病毒（HSV）、人类免疫缺陷病毒（HIV）或痘苗病毒适当感染。通过细胞荧光测定法和细胞毒性测定法评估培养物中分化的NK细胞的扰动情况。观察到，单纯疱疹病毒1型（HSV-1）感染和痘苗病毒感染时，成熟NK细胞上自然细胞毒性受体的表达增加，细胞溶解活性增强，而单链RNA慢病毒（HIV-1）感染时，NK细胞表型和细胞毒性活性均未受到明显调节。在白细胞介素12（IL-12）和白细胞介素15（IL-15）浓度恒定的情况下，观察到的效应不需要细胞接触，涉及干扰素α（IFN-α），且添加Toll样受体9（TLR9）激动剂不能重现该效应，TLR9拮抗剂也不能阻断该效应。NK细胞前体发育部位的病毒复制可能因入侵病毒与成熟NK细胞之间的相互作用而产生不同结果。因此，NK细胞前体可能参与对双链DNA病毒的免疫反应，并可能有助于有效控制病毒感染。
