Aging is associated with a numerical and functional decline in plasmacytoid dendritic cells, whereas myeloid dendritic cells are relatively unaltered in human peripheral blood
Introduction
Dendritic cells (DC) are considered “professional” antigen presenting cells (APC) because of their abilities to capture, process, and present antigens to T cells [1]. DC can express high levels of major histocompatibility complex (MHC) and co-stimulatory molecules that activate T cells, including naïve T cells [2]. In addition, DC can secrete chemokines and cytokines that attract T cells and stimulate T cell growth [[3], [4], [5], [6]]. Based on their lineage origins, DC in human peripheral blood can be categorized into two major subsets, myeloid DC (mDC) and plasmacytoid DC (pDC). Expression of myeloid lineage markers such as CD11c are characteristic of mDC, whereas characteristic lymphoid marker expression of pDC are pre–T-cell receptor (pTα) and Spi-B [[7], [8], [9]]. Different subsets of the Toll-like receptor (TLR) family are expressed in mDC and pDC [10], with mDC selectively expressing TLR 1–6, 10 and pDC primarily expressing TLR 7–9 [11]. In addition to their phenotypic differences, mDC and pDC have distinct functions. For example, influenza virus or herpes simplex virus infection causes stimulation of mDC to secrete interleukin (IL)–6, tumor necrosis factor (TNF)–α, and IL-12, while their stimulation of pDC leads to secretion of interferon (IFN)–α [[12], [13], [14], [15]]. The secretion of IFN-α stimulates natural killer (NK) cells and augments the IFN-γ secretion from type 1 CD4+ T helper cells (TH1) and CD8+T cells, a hallmark of a type 1 T cell response (Th1 response) [[16], [17]]. Consequently, the numbers present, ratio, and functional status of mDC and pDC subsets can influence the innate immune response and the subsequent downstream adaptive immune response.
Elderly persons are particularly susceptible to infection and death from infectious pathogens. For example, more than 90% of the annual influenza virus–related deaths occur among persons more than over 64 years old [18]. The decline in cell-mediated immune responses, particularly the cytotoxic T-cell immune response, is largely believed to be responsible for the increased morbidity and mortality from infectious diseases in elderly individuals [[19], [20]]. Therefore, because DC play a pivotal role in T-cell activation and regulation, it is important to understand age-related changes in numbers and functional status of DC. Previous studies examining the role of DC in human aging have resulted in conflicting results [21]. In one study for mDC, it was reported that elderly subjects had lower numbers of mDC in their peripheral blood compared with young subjects, and mDC from elderly subjects secreted less IL-12 than young subjects after stimulation by lipopolysaccaride (LPS) [22]. In contrast, this age-related decline in mDC in peripheral blood was not observed in the report by Agrawal et al. [23]. In addition, monocyte-derived DC (MDDC) generated in vitro, which resemble mDC in peripheral blood, were reported to have no age-related changes in phenotype or function between young and elderly donor subjects [24]. However, the study by Agrawal et al. demonstrated that MDDC from elderly persons were impaired in pro-inflammatory cytokine secretion and phagocytosis [23]. With regard to pDC, it was reported that aging was associated with a decline in frequency and absolute cell counts in pDC found in peripheral blood [[25], [26]]. However, a recent paper by Della Bella et al. showed that the number of pDC in peripheral blood was not affected by aging [22]. To date, there is no consensus as to how DC subsets are affected by the aging process.
In this study, we obtained mDC and pDC in peripheral blood from subjects of different age and health status. For comparison, the numbers of each subset present and their functional ability to secrete IL-12, IFN-α, and other inflammatory cytokines upon stimulation were determined. We observed that healthy aging was associated with a decline in numbers and functions of pDC, whereas the numbers and function of mDC in the same groups were relatively unaffected. In contrast to aging with sustained health, aging with declining health was associated with a significant decline in the numbers of peripheral blood mDC. In concordance with the age-related changes in function of mDC and pDC, we also found that the proportion of pDC positive for TLR-7 or TLR-9 pDC were reduced, whereas the proportion of TLR-2 and TLR-4 positive mDC were unaltered with aging.
Section snippets
Recruitment and blood samples
The studies were conducted in three subject populations, healthy elderly, healthy young and elderly with underlying disease. The elderly groups were classified using the Canadian Study of Health and Aging (CSHA) categories 1 and 2 for the healthy elderly (fit and well respectively), and categories 5 and 6 for those with underlying disease, which CSHA qualifies as mildly or moderately frail [28]. The healthy populations were independently living volunteers. The exclusion criteria for healthy
Healthy aging is associated with a selective decline in pDC frequency, whereas the mDC frequency remains constant
The numbers of mDC and pDC in total PBMC from healthy young (n = 52; mean age, 28 years) and elderly subjects (n = 75; mean age, 74 years) were quantified using four-color flow cytometry. Figure 1A illustrates a representative dot plot showing the mDC and pDC population in PBMC using CD123 and CD11c as markers. The frequency of pDC in healthy elderly subjects was 28.6% less than that of the healthy young counterparts (median, 0.14% and 0.10% in young and elderly respectively, p = 0.016, Fig. 1
Discussion
We observed a numerical and functional decline in pDC with age. The decline in the numbers of pDC that we demonstrated was not associated with a decrease in the numbers of mDC, suggesting a selective impact on pDC during the healthy aging process. Interestingly, a similar phenomenon has been reported in children during the first decade of life, whose pDC numbers decline rapidly (close to a 2.5-fold decline) whereas the numbers of mDC remain relatively stable [[34], [35]]. Conflicting findings
Acknowledgments
This study was funded by the Commonwealth Health Research Board (Y.D.), and in part by the National Institute of Allergy and Infectious Diseases National Institutes of Health (Y.D., R21AI058004).
We thank Noeline Guillaume for technical assistance. The authors also thank Kimberly Dorsch and Melody Siss for excellent support for subject recruitment and clinical coordination, and Dr. Ann Campbell for thoughtful comments. We also thank Aventis and Bioject Inc. for support through access to blood
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Stefan Gravenstein is currently at the University Medicine Foundation, Alpert Medical School of Brown University, and Quality Partners of Rhode Island, Providence, Rhode Island, USA.