Abstract
Aging leads to dysregulation of multiple components of the immune system that results in increased susceptibility to infections and poor response to vaccines in the aging population. The dysfunctions of adaptive B and T cells are well documented, but the effect of aging on innate immunity remains incompletely understood. Using a heterogeneous population of peripheral blood mononuclear cells (PBMCs), we first undertook transcriptional profiling and found that PBMCs isolated from old individuals (≥ 65 years) exhibited a delayed and altered response to stimulation with TLR4, TLR7/8, and RIG-I agonists compared to cells obtained from adults (≤ 40 years). This delayed response to innate immune agonists resulted in the reduced production of pro-inflammatory and antiviral cytokines and chemokines including TNFα, IL-6, IL-1β, IFNα, IFNγ, CCL2, and CCL7. While the major monocyte and dendritic cell subsets did not change numerically with aging, activation of specific cell types was altered. PBMCs from old subjects also had a lower frequency of CD40+ monocytes, impaired up-regulation of PD-L1 on monocytes and T cells, and increased expression of PD-L2 and B7-H4 on B cells. The defective immune response to innate agonists adversely affected adaptive immunity as TLR-stimulated PBMCs (minus CD3 T cells) from old subjects elicited significantly lower levels of adult T-cell proliferation than those from adult subjects in an allogeneic mixed lymphocyte reaction (MLR). Collectively, these age-associated changes in cytokine, chemokine and interferon production, as well as co-stimulatory protein expression could contribute to the blunted memory B- and T-cell immune responses to vaccines and infections.
Highlights
In the United States, the number of individuals over age 65 is estimated to increase to 20% of the total population by the year 2040 (Kinsella & Wan, 2009)
To evaluate the transcriptional profiles elicited by individuals’ innate agonists on the integrity of human pattern recognition receptors (PRRs) signaling, peripheral blood mononuclear cells (PBMCs) were isolated from healthy nonfrail adults and old donors (n = 8/group)
Cells were stimulated for 6 and 24 hours (h) with LPS (TLR4), CLO97 (TLR7/8), poly I:C complexed with Lyovec (MDA-5/RIGI), or 50-pppRNA complexed with Lyovec (RIG-I), and the scope of PRR responses to innate agonist stimulation was evaluated by microarray analysis using Illumina BeadChips
Summary
In the United States, the number of individuals over age 65 is estimated to increase to 20% of the total population by the year 2040 (Kinsella & Wan, 2009). Aging has been linked to shift in absolute numbers of innate immune cells (including monocytes, DCs, and NK cells), impaired recruitment of these cells to site of infection, reduced phagocytosis by monocytes/macrophages, as well as altered production of interferons, chemokines, and cytokines, and altered Toll-like receptor (TLR) expression (Gomez et al, 2005; Panda et al, 2009; Solana et al, 2012) These alterations suggest possible age-related dysfunction in PRRs responses; no clear consensus has been reached in defining age-related innate immune defects, in part due to the difficulty to extrapolate between mouse and human studies, the use of individual cell
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