Age-Associated Decrease in TLR Function in Primary Human Dendritic Cells Predicts Influenza Vaccine Response

Abstract

We evaluated Toll-like receptor (TLR) function in primary human dendritic cells from 104 young (age 21–30) and older (≥ 65 years) individuals. We used multicolor flow cytometry and intracellular cytokine staining of myeloid (mDC) and plasmacytoid (pDC) DCs and found substantial decreases in older, compared to young individuals in TNF-α, IL-6 and/or IL-12 (p40) production in mDCs and in TNF-α and IFN-α production in pDCs in response to TLR1/2, TLR2/6, TLR3, TLR5, and TLR8 engagement in mDCs and TLR7 and TLR9 in pDCs. These differences were highly significant after adjustment for heterogeneity between young and older groups (e.g. gender, race, body mass index [BMI], number of comorbid medical conditions) using mixed effect statistical modeling. Studies of surface and intracellular expression of TLR proteins, and of TLR gene expression in purified mDCs and pDCs revealed potential contributions for both transcriptional and post-transcriptional mechanisms in these age-associated effects. Moreover, intracellular cytokine production in the absence of TLR ligand stimulation was elevated in cells from older, compared to young individuals, suggesting a dysregulation of cytokine production that may limit further activation by TLR engagement. Our results provide evidence for immunosenescence in dendritic cells; notably, defects in cytokine production were strongly associated with poor antibody response to influenza immunization, a functional consequence of impaired TLR function in the aging innate immune response.

Role of human Toll‐like receptors in naturally occurring influenza A infections

“…Nevertheless, recent studies have shown that TLR's role in regulating the adaptive responses can be harnessed to boost immunogenicity of influenza vaccines (e.g., TLR9 or TLR7 ligands as adjuvants). This may be particularly useful in the elderly and the immunologically naïve vaccinees 4, 33, 34, 35, 36, 37, 38, 39, 40. Our data in natural influenza provide additional support to this new vaccination approach.…”

“…Factors determining TLR expression in an individual should be further studied 3, 42. We report that in some old patients (>65 years of age, P  = 0·025), despite successful cytokine and ligand stimulation studies, the number of DCs in circulation was too few and signals too weak (due to aging and/or site “migration”) to allow full‐range TLR analysis 6, 39. The conclusions were unlikely affected, however, as these were balanced between the age‐matched cases/controls ( P  = 0·768).…”

Phylogenetic analysis of the human antibody repertoire reveals quantitative signatures of immune senescence and aging

“…Notable changes contributing to immunosenescence include, among others, decreased proliferation of lymphocytes, reduced T-cell receptor repertoire, and defects in antibody production (1,2). This phenomenon contributes to an age-related increase in susceptibility to viral and bacterial infections and decreased response to vaccination (3)(4)(5).…”

Safety assessment of adjuvanted vaccines: Methodological considerations

“…In the elderly, antibody responses to vaccines are slower and not as strong as those in younger people, and T-cell subpopulations are not very responsive to vaccines, which may impair the ability to achieve protective immunity after vaccination. 20,21 At an individual level the assessment of safety may be different in na€ ıve versus primed subjects: for example, pre-existing immunity to a specific antigen may cause lower or higher reactogenicity on re-exposure. The safety evaluation will also be influenced by whether the individual is immune-compromised or has underlying morbidities compared to healthy individuals, and by their physiological status: for example, during pregnancy the maternal immune system is altered to tolerate the semi-allogeneic fetus.…”