Elsevier

Human Immunology

Volume 70, Issue 10, October 2009, Pages 777-784
Human Immunology

Aging is associated with a numerical and functional decline in plasmacytoid dendritic cells, whereas myeloid dendritic cells are relatively unaltered in human peripheral blood

https://doi.org/10.1016/j.humimm.2009.07.005Get rights and content

Abstract

Dendritic cells (DC) are potent antigen-presenting cells that initiate and regulate T-cell responses. In this study, the numbers and functional cytokine secretions of plasmacytoid and myeloid DC (pDC and mDC, respectively) in peripheral blood from young and elderly subjects were compared. Overall, pDC numbers in peripheral blood were lower in healthy elderly compared with healthy young subjects (p = 0.016). In response to influenza virus stimulation, isolated pDC from healthy elderly subjects secreted less interferon (IFN)–α compared with those from healthy young subjects. The decline in IFN-α secretion was associated with a reduced proportion of pDC that expressed Toll-like receptor–7 or Toll-like receptor-9. In contrast, there was little difference in the numbers and cytokine secretion function between healthy young and healthy elderly subjects (p = 0.82). However, in peripheral blood from frail elderly subjects, the numbers of mDC were severely depleted as compared with either healthy young or elderly subjects (p = 0.014 and 0.007, respectively). Thus, aging was associated with the numerical and functional decline in pDC, but not mDC, in healthy young versus elderly subject group comparisons, while declining health in the elderly can profoundly impact mDC negatively. Because of the importance of pDC for antiviral responses, the age-related changes in pDC likely contribute to the impaired immune response to viral infections in elderly persons, especially when combined with the mDC dysfunction occurring in those with compromised health.

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.

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