Sridharan Aishwarya, Esposo Marc, Kaushal Khushboo, Tay Jia, Osann Kathyrn, Agrawal Sudhanshu, Gupta Sudhir, Agrawal Anshu
Division of Basic and Clinical Immunology, Department of Medicine, University of California, Irvine, CA 92697, USA.
Age (Dordr). 2011 Sep;33(3):363-76. doi: 10.1007/s11357-010-9191-3. Epub 2010 Oct 16.
Increased susceptibility to infections, particularly respiratory viral infections, is a hallmark of advancing age. The underlying mechanisms are not well understood, and there is a scarcity of information regarding the contribution of the innate immune system, which is the first line of defense against infections. In the present study, we have investigated the effect of advancing age on plasmacytoid dendritic cell (PDC) function because they are critical in generating a robust antiviral response via the secretion of interferons (IFN). Our results indicate that PDCs from the aged are impaired in their capacity to secrete IFN-I in response to influenza virus and CPG stimulation. Additionally, we observed a severe reduction in the production of IFN-III, which plays an important role in defense against viral infections at respiratory mucosal surfaces. This reduction in IFN-I and IFN-III were a result of age-associated impaired phosphorylation of transcription factor, IRF-7. Furthermore, aged PDCs were observed to be impaired in their capacity to induce perforin and granzyme in CD8 T cells. Comparison of the antigen-presenting capacity of aged PDC with young PDC revealed that PDCs from aged subjects display reduced capacity to induce proliferation and IFN-gamma secretion in CD4 and CD8 T cells as compared with PDCs from young subjects. In summary, our study demonstrates that advancing age has a profound effect on PDC function at multiple levels and may therefore, be responsible for the increased susceptibility to infections in the elderly.
对感染，尤其是呼吸道病毒感染的易感性增加是衰老的一个标志。其潜在机制尚未完全了解，而且关于作为抵御感染第一道防线的先天免疫系统的作用的信息也很匮乏。在本研究中，我们研究了衰老对浆细胞样树突状细胞（pDC）功能的影响，因为它们在通过分泌干扰素（IFN）产生强大的抗病毒反应中起关键作用。我们的结果表明，老年pDC对流感病毒和CPG刺激分泌I型干扰素（IFN-I）的能力受损。此外，我们观察到III型干扰素（IFN-III）的产生严重减少，IFN-III在呼吸道黏膜表面抵御病毒感染中起重要作用。IFN-I和IFN-III的这种减少是转录因子IRF-7与年龄相关的磷酸化受损的结果。此外，观察到老年pDC诱导CD8 T细胞中穿孔素和颗粒酶的能力受损。比较老年pDC与年轻pDC 的抗原呈递能力发现，与年轻受试者的pDC相比，老年受试者的pDC在诱导CD4和CD8 T细胞增殖和分泌IFN-γ方面的能力降低。总之，我们的研究表明，衰老在多个水平上对pDC功能有深远影响，因此可能是老年人感染易感性增加的原因。
