Age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response
Open accessAbstract
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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Similar results have been replicated in the response to influenza vaccination across different age groups in humans.
“Similar results have been replicated in the response to influenza vacci nation across different age groups in humans (Panda et al., 2010; Bahadoran et al., 2016).”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Panda et al., 2010
Most studies describe reduced cytokine production by DCs stimulated with Toll-like receptor ligands in vitro, and this defect correlates with reduced vaccination responses.
“Most studies describe reduced cytokine production of DCs stimulated with Toll-like receptor ligands in vitro, a defect that has been correlated with reduced responses to vaccination”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Panda et al., 2010
pDCs from elderly subjects show marked impairment of pro-inflammatory cytokine release upon viral or TLR stimulation, with reduced intracellular TNF-α, IL-6, IL-12, IFN-α, IFN-β and IFN-γ, but phagocytosis appears well preserved.
“pDCs are characterized by a marked impairment of pro-inflammatory cytokine release with aging: pDCs display a reduction in intracellular levels of TNF-α, IL-6 and IL-12, as well as IFN-α, IFN-β and IFN-γ upon viral or TLR stimulation [52, 53]; however, phagocytosis appears well preserved [41].”
From Aging of the immune system: Focus on inflammation and vaccination (2016) · cites this paper as [52]
Reduced production of cytokines by pDCs from older people is caused by defects in TLR signaling pathways.
“This has potentially important implications, because the reduced production of cytokines by pDCs from older people, caused by defects in TLR signaling pathways, is associated with an ineffective antibody response to influenza vaccination (221).”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [221]
Reduced production of cytokines by pDCs from older people is associated with an ineffective antibody response to influenza vaccination.
“This has potentially important implications, because the reduced production of cytokines by pDCs from older people, caused by defects in TLR signaling pathways, is associated with an ineffective antibody response to influenza vaccination (221).”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [221]
Altered PRR expression and/or changes in downstream signaling cascades may underlie dysregulated DC responses in older persons.
“Altered PRR expression and/or changes in downstream signaling cascades may underlie dysregulated DC responses in older persons (114, 116).”
From Aging and Lung Disease (2020) · cites this paper as [116]
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Pattern recognition receptors: function, regulation and therapeutic potential
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Exploring Single-Cell Data with Deep Multitasking Neural Networks
Amodio, M., van Dijk, D., Srinivasan, K., Chen, W. S., Mohsen, H., Moon, K. R., Campbell, A., Zhao, Y.-J., Wang, X.-M., Venkataswamy, M., et al. (2017) · Nature Methods · doi:10.1038/s41592-019-0576-7 · Cited by 288 · see citing works
Self-citationFranceschi, C., Salvioli, S., Garagnani, P., de Eguileor, M., Monti, D., & Capri, M. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00982 · Cited by 290 · see citing works
“Similarly, reduced TLR levels and signaling responses in DCs were found (88).”
BackgroundExercise and the aging immune system
Simpson, R. J., Lowder, T. W., Spielmann, G., Bigley, A. B., LaVoy, E. C., & Kunz, H. (2012) · Ageing Research Reviews · doi:10.1016/j.arr.2012.03.003 · Cited by 281 · see citing works
Meftahi, G. H., Jangravi, Z., Sahraei, H., & Bahari, Z. (2020) · Inflammation Research · doi:10.1007/s00011-020-01372-8 · Cited by 289 · see citing works
“Panda and colleagues in 2010 identified an increase of pro-inflammatory cytokines released from DCs in elderly adults [88].”
BackgroundThe Confluence of Sex Hormones and Aging on Immunity
Gubbels Bupp, M. R., Potluri, T., Fink, A. L., & Klein, S. L. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01269 · Cited by 277 · see citing works
Aging, inflammation, immunity and periodontal disease
Ebersole, J. L., Graves, C. L., González, O. A., Dawson, D. R., Morford, L. A., Emecen‐Huja, P., Hartsfield, J. K., Huja, S. S., Pandruvada, S. N. M., & Wallet, S. M. (2016) · Periodontology 2000 · doi:10.1111/prd.12135 · Cited by 308 · see citing works
“Finally, basal levels of intracellular cytokines in primary myeloid dendritic cells and plasmacytoid dendritic cells are elevated in older individuals compared with younger adults (140).”
Abnormal lung aging in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis
Faner, R., Rojas, M., MacNee, W., & Agustí, A. (2012) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201202-0282pp · Cited by 268 · see citing works
Macrophages in age-related chronic inflammatory diseases
Oishi, Y., & Manabe, I. (2016) · npj Aging and Mechanisms of Disease · doi:10.1038/npjamd.2016.18 · Cited by 262 · see citing works
“Dendritic cells from elderly subjects also express lower levels of Toll-like receptors (TLRs) and produce lower levels of cytokines in response to specific TLR ligands, while the baseline cytokine levels in absence of TLR ligand stimulation are increased, suggesting dysregulated cytokine expression.(26,27) Similarly,…”
BackgroundOh, S. J., Lee, J. K., & Shin, O. S. (2019) · Immune Network · doi:10.4110/in.2019.19.e37 · Cited by 261 · see citing works
“A number of studies show that aging does not alter the number of myeloid DCs (mDCs), but reduce the number and function of plasmacytoid DCs (30-32).”
BackgroundInfluentialImpact of aging on dendritic cell functions in humans
Agrawal, A., & Gupta, S. (2011) · Ageing Research Reviews · doi:10.1016/j.arr.2010.06.004 · Cited by 246 · see citing works
Mx1 reveals innate pathways to antiviral resistance and lethal influenza disease
Pillai, P. S., Molony, R. D., Martinod, K., Dong, H., Pang, I. K., Tal, M. C., Solis, A. G., Bielecki, P., Mohanty, S., Trentalange, M. J., et al. (2016) · Science · doi:10.1126/science.aaf3926 · Cited by 241 · see citing works
Self-citationIBD across the age spectrum—is it the same disease?
Ruel, J., Ruane, D., Mehandru, S., Gower‐Rousseau, C., & Colombel, J. (2013) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2013.240 · Cited by 237 · see citing works
Moro‐García, M. A., Mayo, J. C., Sainz, R. M., & Alonso‐Arias, R. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00339 · Cited by 232 · see citing works
“Moreover, most studies describe a reduced ability to produce cytokines by dendritic cells stimulated through toll-like receptors in vitro, a defect related to low response to vaccination in elderly (48, 49).”
BackgroundMcElhaney, J. E., Zhou, X., Talbot, H. K., Soethout, E., Bleackley, R. C., Granville, D. J., & Pawelec, G. (2012) · Vaccine · doi:10.1016/j.vaccine.2012.01.015 · Cited by 229 · see citing works
“Although the expression of TLR declines with aging [59], the functional consequence of this age-related change remains an area of controversy requiring further investigation [60].”
BackgroundImmune System Dysfunction in the Elderly
Eduardo Fuentes, Q., FUENTES, M., Alarcón, M. A., & Palomo, I. F. (2017) · Anais da Academia Brasileira de Ciências · doi:10.1590/0001-3765201720160487 · Cited by 234 · see citing works
Frasca, D., Diaz, A., Romero, M., Garcia, D., & Blomberg, B. B. (2020) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-011620-034148 · Cited by 226 · see citing works
“Inflammaging induces intrinsic inflammation in immune cells leading to both decreased protective responses against infections and decreased vaccine responses (Bryl et al. 2001, Frasca et al. 2014, Parish et al. 2009).”
BackgroundDysregulation of human Toll-like receptor function in aging
Shaw, A. C., Panda, A., Joshi, S. R., Qian, F., Allore, H. G., & Montgomery, R. R. (2011) · Ageing Research Reviews · doi:10.1016/j.arr.2010.10.007 · Cited by 215 · see citing works
“The most comprehensive study to date of TLR-induced cytokine production in 52 young (21–30) and 52 older (≥65) individuals, using intracellular staining to quantify cytokine levels in primary mDCs and pDCs, evaluated the generation of TNF-α, IL-6, and the p40 subunit shared by IL-12 and IL-23 following stimulation wit…”
InfluentialSelf-citationRecent advances in our understanding of giant cell arteritis pathogenesis
Samson, M., Corbera‐Bellalta, M., Audia, S., Planas‐Rigol, E., Martin, L., Cid, M. C., & Bonnotte, B. (2017) · Autoimmunity Reviews · doi:10.1016/j.autrev.2017.05.014 · Cited by 210 · see citing works
Age-related changes in immune function: Effect on airway inflammation
Busse, P. J., & Mathur, S. K. (2010) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2010.08.011 · Cited by 209 · see citing works
Sleep after Vaccination Boosts Immunological Memory
Lange, T., Dimitrov, S., Bollinger, T., Diekelmann, S., & Born, J. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1100015 · Cited by 201 · see citing works
Metcalf, T. U., Cubas, R. A., Ghneim, K., Cartwright, M. J., Grevenynghe, J. V., Richner, J. M., Olagnier, D. P., Wilkinson, P. A., Cameron, M. J., Park, B. S., et al. (2015) · Aging Cell · doi:10.1111/acel.12320 · Cited by 189 · see citing works
“On the other hand, others have reported no change or lower production in old compared to adult subjects (Gon et al., 1996; van Duin et al., 2007b; Panda et al., 2010).”
BackgroundChougnet, C. A., Thacker, R. I., Shehata, H. M., Hennies, C. M., Lehn, M. A., Lages, C. S., & Janssen, E. M. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1501006 · Cited by 187 · see citing works
Ageing and the border between health and disease
MacNee, W., Rabinovich, R., & Choudhury, G. (2014) · European Respiratory Journal · doi:10.1183/09031936.00134014 · Cited by 188 · see citing works
A Paradoxical Role for Neutrophils in the Pathogenesis of West Nile Virus
Bai, F., Kong, K., Dai, J., Qian, F., Zhang, L., Brown, C. R., Fikrig, E., & Montgomery, R. R. (2010) · The Journal of Infectious Diseases · doi:10.1086/657416 · Cited by 188 · see citing works
“Although immune responses are generally successful at combating infection due to WNV in young immunocompetent individuals, WNV attenuates activation of macrophages [34], and increased susceptibility in the elderly population may be attributable to dysregulation of innate responses in that population [27, 35].”
BackgroundSelf-citationHallmarks of aging and immunosenescence: Connecting the dots
Rodrigues, L. P., Teixeira, V. R., Alencar‐Silva, T., Simonassi-Paiva, B., Pereira, R. W., Pogue, R. E., & Carvalho, J. L. (2021) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2021.01.006 · Cited by 187 · see citing works
Targeting Inflammation and Immunosenescence to Improve Vaccine Responses in the Elderly
Pereira, B. I., Xu, X., & Akbar, A. N. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.583019 · Cited by 182 · see citing works
Aging Affects Human B Cell Responses
Frasca, D., & Blomberg, B. B. (2011) · Journal of Clinical Immunology · doi:10.1007/s10875-010-9501-7 · Cited by 172 · see citing works
“Immunosenescence indicates age-associated immune dysfunctions which occur in both innate and adaptive systems [3–6] and include reduced natural killer cell cytotoxicity on a per cell basis [7], reduced number and/ or function of dendritic cells in blood [6, 8–10], decreased total naive and increased memory T cells [10…”
Sridharan, A., Esposo, M., Kaushal, K., Tay, J., Osann, K., Agrawal, S., Gupta, S., & Agrawal, A. (2011) · AGE · doi:10.1007/s11357-010-9191-3 · Cited by 165 · see citing works
Parallels in Immunometabolic Adipose Tissue Dysfunction with Ageing and Obesity
Trim, W. V., Turner, J. E., & Thompson, D. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00169 · Cited by 169 · see citing works
The immune response to influenza in older humans: beyond immune senescence
McElhaney, J. E., Verschoor, C. P., Andrew, M. K., Haynes, L., Kuchel, G. A., & Pawelec, G. (2020) · Immunity & Ageing · doi:10.1186/s12979-020-00181-1 · Cited by 168 · see citing works
“gagement of TLR1/2, TLR2/6, TLR3, TLR5, and TLR8 in mDCs and TLR7 and TLR9 in pDCs, may be mediated by dysregulated cytokine production [93].”
Aging impairs both primary and secondary RIG-I signaling for interferon induction in human monocytes
Molony, R. D., Nguyen, J. T., Kong, Y., Montgomery, R. R., Shaw, A. C., & Iwasaki, A. (2017) · Science Signaling · doi:10.1126/scisignal.aan2392 · Cited by 154 · see citing works
Self-citationFrasca, D., Diaz, A., Romero, M., & Blomberg, B. B. (2017) · Experimental Gerontology · doi:10.1016/j.exger.2016.12.001 · Cited by 160 · see citing works
Pallikkuth, S., Parmigiani, A., Silva, S. Y., George, V. K., Fischl, M. A., Pahwa, R., & Pahwa, S. G. (2012) · Blood · doi:10.1182/blood-2011-12-396648 · Cited by 162 · see citing works
Dendritic cells of the oral mucosa
Hovav, A.-H. (2013) · Mucosal Immunology · doi:10.1038/mi.2013.42 · Cited by 161 · see citing works
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Self-citationUnderstanding immunosenescence and its impact on vaccination of older adults
Allen, J. C., Toapanta, F. R., Chen, W. H., & Tennant, S. M. (2020) · Vaccine · doi:10.1016/j.vaccine.2020.11.002 · Cited by 157 · see citing works
“older subjects displayed decreased production of pro-inflammatory cytokines, such as IL-6, IL-12, and TNF-α, when stimulated with TLR specific ligands [17].”
BackgroundAge‐associated elevation in TLR5 leads to increased inflammatory responses in the elderly
Qian, F., Wang, X., Zhang, L., Chen, S., Piecychna, M., Allore, H., Bockenstedt, L., Malawista, S., Bucala, R., Shaw, A. C., et al. (2012) · Aging Cell · doi:10.1111/j.1474-9726.2011.00759.x · Cited by 154 · see citing works
“tional effects contribute to the decreases noted in TLR function in DCs in aging (Panda et al., 2010).”
BackgroundResultInfluentialSelf-citationSkeletal muscle regeneration and impact of aging and nutrition
Domingues-Faria, C., Vasson, M.-P., Goncalves-Mendes, N., Boirie, Y., & Walrand, S. (2016) · Ageing Research Reviews · doi:10.1016/j.arr.2015.12.004 · Cited by 157 · see citing works
Influenza vaccine responses in older adults
McElhaney, J. E. (2010) · Ageing Research Reviews · doi:10.1016/j.arr.2010.10.008 · Cited by 155 · see citing works
Salminen, A., Kaarniranta, K., & Kauppinen, A. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03048-x · Cited by 156 · see citing works
Role of Dendritic Cells in Inflammation and Loss of Tolerance in the Elderly
Agrawal, A., Agrawal, S., & Gupta, S. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00896 · Cited by 154 · see citing works
Age-related changes in CD8 T cell homeostasis and immunity to infection
Nikolich‐Žugich, J., Li, G., Uhrlaub, J. L., Renkema, K. R., & Smithey, M. J. (2012) · Seminars in Immunology · doi:10.1016/j.smim.2012.04.009 · Cited by 153 · see citing works
Qian, F., Wang, X., Zhang, L., Lin, A., Zhao, H., Fikrig, E., & Montgomery, R. R. (2011) · The Journal of Infectious Diseases · doi:10.1093/infdis/jir048 · Cited by 151 · see citing works
“Plasmacytoid DCs (pDCs) were enriched from PBMCs ( 4-6 x10(5) pDCs/50 mL blood) by magnetic bead depletion of CD14- and CD19-positive cells and positive selection with antiBDCA4 beads (Miltenyibiotec) [21].”
BackgroundMethodResultInfluentialSelf-citationVu, R., Jin, S., Sun, P., Haensel, D., Nguyen, Q., Dragan, M., Kessenbrock, K., Nie, Q. H., & Dai, X. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111155 · Cited by 149 · see citing works
“These findings suggest that DCs in aged mouse skin may be more likely to migrate to LNs, a feature reminiscent of DCs from aged human subjects that exhibit enhanced basal-level inflammatory responses (Agrawal et al., 2009; Panda et al., 2010).”
Immunosenescence and inflammaging: Mechanisms and role in diseases
Ajoolabady, A., Praticò, D., Tang, D., Zhou, S., Franceschi, C., & Ren, J. T. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102540 · Cited by 159 · see citing works
Lefevre, M., Racedo, S. M., Ripert, G., Housez, B., Cazaubiel, M., Maudet, C., Jüsten, P., Marteau, P., & Urdaci, M. C. (2015) · Immunity & Ageing · doi:10.1186/s12979-015-0051-y · Cited by 147 · see citing works
“For innate dysfunction, it has been described that the function of natural killer cells, dendritic cells [2], macrophages [3] and neutrophils [4] decrease in the elderly.”
BackgroundSARS-CoV-2–associated ssRNAs activate inflammation and immunity via TLR7/8
Salvi, V., Nguyen, H. O., Sozio, F., Schioppa, T., Gaudenzi, C., Laffranchi, M., Scapini, P., Passari, M., Barbazza, I., Tiberio, L., et al. (2021) · JCI Insight · doi:10.1172/jci.insight.150542 · Cited by 148 · see citing works
“Since the magnitude of TLR activation differs in individuals, such as elderly 221 people, differences in TLR activation may help explain differences in the quality of the antiviral 222 immune response independently of SAMP potency (37).”
BackgroundHagan, T., Gerritsen, B., Tomalin, L. E., Fourati, S., Mulè, M. P., Chawla, D. G., Rychkov, D., Henrich, E., Miller, H. E. R., Diray‐Arce, J., et al. (2022) · Nature Immunology · doi:10.1038/s41590-022-01328-6 · Cited by 148 · see citing works
Self-citationParadoxical changes in innate immunity in aging: recent progress and new directions
Montgomery, R. R., & Shaw, A. C. (2015) · Journal of Leukocyte Biology · doi:10.1189/jlb.5mr0315-104r · Cited by 147 · see citing works
“Changes in TLRinduced expression of costimulatory molecules in monocytes and of proinflammatory cytokines in primary mDC and pDCs were also associated with impaired influenza vaccine antibody response [7, 14].”
BackgroundSelf-citationAging and its impact on innate immunity and inflammation: Implications for periodontitis
Hajishengallis, G. (2013) · Journal of Oral Biosciences · doi:10.1016/j.job.2013.09.001 · Cited by 145 · see citing works
“N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript Table 1 Effects of aging on phagocytes and antigen-presenting cells Functional activity Cell type Neutrophils Monocytes/Macrophages Dendritic cells Red…”
BackgroundInfluentialThe Gracefully Aging Immune System
Boraschi, D., Aguado, M. T., Dutel, C., Goronzy, J. J., Louis, J. A., Grubeck‐Loebenstein, B., Rappuoli, R., & Giudice, G. D. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3005624 · Cited by 133 · see citing works
Immunotherapy comes of age: Immune aging & checkpoint inhibitors
Elias, R., Karantanos, T., Sira, E., & Hartshorn, K. L. (2017) · Journal of Geriatric Oncology · doi:10.1016/j.jgo.2017.02.001 · Cited by 133 · see citing works
Exploiting Mucosal Immunity for Antiviral Vaccines
Iwasaki, A. (2016) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032414-112315 · Cited by 132 · see citing works
de Bourcy, C. F. A., Angel, C. J. L., Vollmers, C., Dekker, C. L., Davis, M. M., & Quake, S. R. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1617959114 · Cited by 127 · see citing works
“Notable changes contributing to immunosenescence include, among others, decreased proliferation of lymphocytes, reduced T-cell receptor repertoire, and defects in antibody production (1, 2).”
BackgroundImpact of aging on antigen presentation cell function of dendritic cells
Wong, C. K., & Goldstein, D. R. (2013) · Current Opinion in Immunology · doi:10.1016/j.coi.2013.05.016 · Cited by 129 · see citing works
Association of human papillomavirus infection and inflammation in cervical cancer
Hemmat, N., & Baghi, H. B. (2019) · Pathogens and Disease · doi:10.1093/femspd/ftz048 · Cited by 129 · see citing works
Immunosenescence and Challenges of Vaccination against Influenza in the Aging Population.
Reber, A. J., Chirkova, T., Kim, J. H., Cao, W., Biber, R., Shay, D. K., & Sambhara, S. R. (2012) · Europe PMC (PubMed Central) · Cited by 128 · see citing works
Lambert, N. D., Ovsyannikova, I. G., Pankratz, V. S., Jacobson, R. M., & Poland, G. A. (2012) · Expert Review of Vaccines · doi:10.1586/erv.12.61 · Cited by 127 · see citing works
Neuzillet, C., Marchais, M., Vacher, S., Hilmi, M., Schnitzler, A., Meseure, D., Leclère, R., Lecerf, C., Dubot, C., Jeannot, E., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-86816-9 · Cited by 128 · see citing works
Dhakal, S., & Klein, S. L. (2019) · Journal of Virology · doi:10.1128/jvi.00797-19 · Cited by 123 · see citing works
“Lower expression of CD80 costimulatory molecules in activated monocytes (31), a reduced number of plasmacytoid dendritic cells and a generalized decrease in Toll-like receptor 7 (TLR7)- and TLR8-induced cytokines (alpha interferon [IFN- ] and interleukin-12p40 [IL-12p40]) in dendritic cells (32), and impaired inflamma…”
BackgroundSkloot, G. S., Busse, P. J., Braman, S. S., Kovacs, E. J., Dixon, A. E., Fragoso, C. A. V., Scichilone, N., Prakash, Y. S., Pabelick, C. M., Mathur, S. K., et al. (2016) · Annals of the American Thoracic Society · doi:10.1513/annalsats.201608-658st · Cited by 118 · see citing works
Salminen, A. (2021) · Journal of Molecular Medicine · doi:10.1007/s00109-021-02123-w · Cited by 124 · see citing works
“[125] also observed that mouse MDSCs actively secreted IL-10 cytokines which downregulated IL-12 production from DCs, thus suppressing their capacity to stimulate the functions of T cells.”
BackgroundInfluentialAging induces B cell defects and decreased antibody responses to influenza infection and vaccination
Frasca, D., & Blomberg, B. B. (2020) · Immunity & Ageing · doi:10.1186/s12979-020-00210-z · Cited by 130 · see citing works
Boyd, A. R., Shivshankar, P., Jiang, S., Berton, M. T., & Orihuela, C. J. (2012) · Experimental Gerontology · doi:10.1016/j.exger.2012.04.004 · Cited by 117 · see citing works
“Importantly, reduced dendritic cell TLR function was correlated with decreased antibody responses in elderly humans following influenza immunization; thereby indicating that TLR dysfunction might also contribute to the age-related decline in vaccine efficacy (Panda et al., 2010).”
BackgroundHigh TNF-α levels in resting B cells negatively correlate with their response
Frasca, D., Diaz, A., Romero, M., Landin, A. M., & Blomberg, B. B. (2014) · Experimental Gerontology · doi:10.1016/j.exger.2014.01.004 · Cited by 115 · see citing works
“, 2009; Vallejo, 2005) and innate cells (Panda et al., 2010; Solana et al., 2006; Sridharan et al., 2010) have decreased function with age.”
Hou, Y., Chen, M., Bian, Y., Hu, Y., Chuan, J., Zhong, L., Zhu, Y., & Tong, R. (2024) · npj Vaccines · doi:10.1038/s41541-024-00874-4 · Cited by 116 · see citing works
“…and TLR7 in pDC leads to reduced cytokine secretion after activation; nevertheless, the expression of TLR1, 2, 4, 5, 6, and 9 did not change with age, and decreased cytokine secretion was also observed, suggesting that other unknown factors besides TLR expression in fl uence the immune response 25 .”
BackgroundImmunosenescence is both functional/adaptive and dysfunctional/maladaptive
Fülöp, T., Larbi, A., Hirokawa, K., Cohen, A. A., & Witkowski, J. M. (2020) · Seminars in Immunopathology · doi:10.1007/s00281-020-00818-9 · Cited by 106 · see citing works
Glioblastoma as an age-related neurological disorder in adults
Kim, M., Ladomersky, E., Mozny, A., Kocherginsky, M., O’Shea, K., Reinstein, Z. Z., Zhai, L., Bell, A., Lauing, K. L., Bollu, L. R., et al. (2021) · Neuro-Oncology Advances · doi:10.1093/noajnl/vdab125 · Cited by 108 · see citing works
Innate immunesenescence: underlying mechanisms and clinical relevance
Hazeldine, J., & Lord, J. M. (2015) · Biogerontology · doi:10.1007/s10522-014-9514-3 · Cited by 104 · see citing works
“For instance, both the intracellular levels of TNF-a, IL-6 and IL-12 and the secretion of type I and III interferons by pDCs from older adults following either TLR or viral stimulation have been shown to be significantly lower than the corresponding levels recorded for pDCs from their younger counterparts (Jing et al.…”
InfluentialWeinberger, B., & Grubeck-Loebenstein, B. (2012) · Clinical Microbiology and Infection · doi:10.1111/j.1469-0691.2012.03944.x · Cited by 104 · see citing works
“A recent study using primary myeloid and plasmacytoid dendritic cells showed that there is an age-related defect in the production of several cytokines after stimulation via almost all TLRs tested, which is correlated with the generation of protective antibodies after influenza vaccination [90].”
BackgroundA comparative review of aging and B cell function in mice and humans
Scholz, J. L., Diaz, A., Riley, R. L., Cancro, M. P., & Frasca, D. (2013) · Current Opinion in Immunology · doi:10.1016/j.coi.2013.07.006 · Cited by 103 · see citing works
“Many studies have shown that the age-related decrease in the response to influenza vaccination is correlated with the decrease in T cell [59] and dendritic cell [60] function.”
BackgroundJose, S. S., Bendíčková, K., Kepák, T., Křenová, Z., & Frič, J. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01078 · Cited by 105 · see citing works
Duggal, N. A., Upton, J., Phillips, A. C., Sapey, E., & Lord, J. (2013) · Aging Cell · doi:10.1111/acel.12114 · Cited by 110 · see citing works
“induced cytokine production in monocytes, macrophages and dendritic cells (Panda et al., 2010), including reduced TLR4 expression and function on macrophages and dendritic cells with age (Renshaw et al.”
BackgroundStout-Delgado, H. W., Vaughan, S. E., Shirali, A. C., Jaramillo, R. J., & Harrod, K. S. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1103051 · Cited by 100 · see citing works
Deshpande, R. P., Sharma, S., & Watabe, K. (2020) · Cancers · doi:10.3390/cancers12102983 · Cited by 101 · see citing works
“Similarly, the secretion of another cytokine, IL-12, by dendritic cells was reduced in older adults which caused decreased INF-gamma secretion by T cells thereby impeding its cytotoxic activity [78].”
BackgroundFactors affecting immune responses to the influenza vaccine
Castrucci, M. R. (2017) · Human Vaccines & Immunotherapeutics · doi:10.1080/21645515.2017.1338547 · Cited by 97 · see citing works
“cellular and humoral immunity and thus influenza-vaccineinduced antibody production.(35) The function and number of”
BackgroundFreer, G., & Rindi, L. (2013) · Methods · doi:10.1016/j.ymeth.2013.03.035 · Cited by 97 · see citing works
Antidepressants normalize elevated Toll-like receptor profile in major depressive disorder
Hung, Y.-Y., Huang, K.-W., Kang, H., Huang, G. Y.-L., & Huang, T. (2015) · Psychopharmacology · doi:10.1007/s00213-015-4087-7 · Cited by 96 · see citing works
“Age has been reported as a confounder in TLR3, TLR7, and TLR8 mRNA expression (Panda et al. 2010); thus, an ageadjusted analysis of covariance (ANCOVA) was used to compare differences in the expression of these isoforms.”
Aging, immune senescence, and immunotherapy: a comprehensive review
Elias, R., Hartshorn, K., Rahma, O., Lin, N., & Snyder-Cappione, J. E. (2018) · Seminars in Oncology · doi:10.1053/j.seminoncol.2018.08.006 · Cited by 96 · see citing works
- Authors
- Panda, A., Qian, F., Mohanty, S., van Duin, D., Newman, F. K., Zhang, L., Chen, S., Towle, V., Belshe, R. B., Fikrig, E., Allore, H. G., Montgomery, R. R., & Shaw, A. C.
- Affiliations
- Section of Infectious Diseases
- Section of Rheumatology
- Saint Louis University (US)
- Department of Internal Medicine
- Howard Hughes Medical Institute (US)
- Corresponding author
- Panda, Alexander
- Mohanty, Subhasis
- Fikrig, Erol
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-03-01
- Volume
- 184
- Issue
- 5
- Pages
- 2518-2527
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC3867271
- OpenAlex
- W1907043835
- Cited by
- 548
- References
- 46
- Citations by year
- 2026: 12 · 2025: 32 · 2024: 25 · 2023: 32 · 2022: 42 · 2021: 46 · 2020: 34 · 2019: 26 · 2018: 28 · 2017: 35 · 2016: 34 · 2015: 32 · 2014: 38 · 2013: 46 · 2012: 35
- FWCI
- 17.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- John A. Hartford Foundation
- Hartford Foundation for Public Giving
- Yale University
- University of Washington
- National Institutes of Health (n01ai50031-6-0-1, AG021342)
- National Institute on Aging (P30AG021342)
- National Institute of Allergy and Infectious Diseases (N01 AI500031, N01 AI050031, N01-AI-50031, AI070343, U01AI070343)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Keywords
- immunosenescence, dendritic cells, aging, influenza vaccine response, myeloid dendritic cells, plasmacytoid dendritic cells, cytokine production, TLR7, TLR9, TLR3, TLR5, TLR8, TLR1/2, TLR2/6, TNF-α, interferon-alpha, IL-12, antibody response, innate immunity
- MeSH terms
- Adult, Age Factors, Aged, Aged, 80 and over, Antibodies, Viral, Dendritic Cells, Female, Flow Cytometry, Humans, Influenza Vaccines, Male, Middle Aged, Tumor Necrosis Factor-alpha, Interleukin-6, Linear Models, Cytokines, Reverse Transcriptase Polymerase Chain Reaction, Toll-Like Receptors, Influenza A Virus, H1N1 Subtype, Interleukin-12 Subunit p40, Young Adult
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