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

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)-alpha compared with those from healthy young subjects. The decline in IFN-alpha 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.

Fig. 1

Quantifications of the numbers of mDC and pDC in healthy young, healthy elderly, and frail elderly subjects (for subject numbers and ages, see data presented Table 1). The numbers of mDC and pDC were quantified using flow cytometry in PBMC stained with lineage markers (FITC), CD123 (PE), HLA-DR (PerCP), and CD11c (APC). (A) Representative dot plot showing the mDC (upper left) and pDC (lower right) populations. (B) Numbers of pDC and mDC in total PBMC from different groups. Horizontal bars represent geometric mean values. *p < 0.05. Median, mean, and standard error (SE) are listed under each group.

Fig. 2

Comparison of TLR expression by pDC and mDC from healthy young and healthy elderly subjects. Fourteen healthy young (mean age, 34.3 years) and 17 healthy elderly subjects (mean age, 72.6 years) were recruited for testing the TLR-2 and TLR-4 expression on cells surface of mDC. The intracellular expression of TLR-7 and TLR-9 in pDC were compared between 13 young (mean age, 26.1 years) and 13 elderly (mean age, 69.4 years) subjects. PMBC isolated from these subjects were stained with lineage markers (FITC), HLA-DR (PerCP), CD11c (APC), and TLR (PE) of interest. Data shown are mean values from each age group with standard errors shown in error bars. *p ≤ 0.05.

Fig. 3

IFN-α and IL-12 secretion from pDC or mDC, respectively, from healthy young and healthy elderly subjects. Eighteen healthy young (mean age, 36.1) and 19 healthy elderly subjects (mean age, 74.4) were recruited. PBMC isolated from these subjects were stimulated with influenza virus infection or CpG (for pDC to secrete IFN-α), or poly I:C (for mDC to secrete IL-12). Stimulated PBMC were subjected to intracellular cytokine staining for IL-12 or IFN-α. Only DC (lineage marker–negative and HLA-DR–positive cells) were gated for analysis. (A) Representative dot plot illustrating the distinct pattern of cytokine secretion by mDC and pDC upon stimulation. (B–D, left panels) Frequencies of IFN-α⁺-pDC (B and C) or IL-12⁺-mDC (D) in PBMC upon stimulation in young and elderly group. (B–D, right panels) are the mean fluorescent levels (MFL) of corresponding cytokine. In unstimulated PBMC, the numbers of IFN-α or IL-12 positive pDC or mDC was below detectable levels (0.01%). Horizontal bars denote medians. *p < 0.05.