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

Journal of Immunology - Tập 184 Số 5 - Trang 2518-2527 - 2010
Alexander Panda1, Feng Qian2, Subhasis Mohanty1, David van Duin1, Frances K. Newman3, Lin Zhang2, Shu Chen4, Virginia Towle4, Robert B. Belshe3, Erol Fikrig1,5, Heather Allore4, Ruth R. Montgomery2, Albert C. Shaw1
1Section of Infectious Diseases
2Section of Rheumatology
3‡Division of Infectious Diseases and Immunology, Saint Louis University School of Medicine, St. Louis, MO 63104
4Department of Internal Medicine and
5§Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520; and

Tóm tắt

Abstract We evaluated TLR function in primary human dendritic cells (DCs) from 104 young (age 21–30 y) and older (≥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-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, 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.

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Journal of Immunology

Tập 184 Số 5

2518-2527

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