Age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response.
We evaluated TLR function in primary human dendritic cells (DCs) from 104 young (age 21-30 y) and older (> or =65 y) individuals. We used multicolor flow cytometry and intracellular cytokine staining of myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) and found substantial decreases in older compared with young individuals in TNF-alpha, IL-6, and/or IL-12 (p40) production in mDCs and in TNF-alpha and IFN-alpha 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, 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 posttranscriptional mechanisms in these age-associated effects. Moreover, intracellular cytokine production in the absence of TLR ligand stimulation was elevated in cells from older compared with young individuals, suggesting a dysregulation of cytokine production that may limit further activation by TLR engagement. Our results provide evidence for immunosenescence in DCs; notably, defects in cytokine production were strongly associated with poor Ab response to influenza immunization, a functional consequence of impaired TLR function in the aging innate immune response.
Panda
Alexander
A
Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT 06520, USA.
Qian
Feng
F
Mohanty
Subhasis
S
van Duin
David
D
Newman
Frances K
FK
Zhang
Lin
L
Chen
Shu
S
Towle
Virginia
V
Belshe
Robert B
RB
Fikrig
Erol
E
Allore
Heather G
HG
Montgomery
Ruth R
RR
Shaw
Albert C
AC
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000914:Antibodies, Viral / Q000097:blood; D016207:Cytokines / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D007252:Influenza Vaccines / Q000276:immunology*; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D055815:Young Adult
D000914:Antibodies, Viral; D016207:Cytokines; D007252:Influenza Vaccines; D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha