Epigenomics of human CD8 T cell differentiation and aging
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Genome-wide epigenetic profiling defines the transcriptional networks involved in T cell aging.
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Old central memory CD8+ T cells had features of effector T cell differentiation.
“old central memory CD8+ T cells had features of effector T cell differentiation”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Moskowitz et al., 2017
Separate analysis of CD28+ and CD28− CD8+ T cells in young and old individuals was consistent with old CD28+CD8+ T cells being more differentiated, as also suggested by epigenetic studies.
“A separate analysis of CD28+ and CD28− CD8+ T cells in young and old individuals were consistent with the model that old CD28+CD8+ T cells were more differentiated (Lazuardi et al., 2009) as also suggested by the epigenetic studies of CD8+ T cell subsets (Moskowitz et al., 2017).”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Moskowitz et al., 2017
The shift in naive and central memory CD8+ T cells was mediated by increased accessibility at bZIP family sites and closure of Ets family transcription factor binding sites.
“both mediated by an increase in sites accessible to bZIP family and a closure of Ets family transcription factor binding sites.”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Moskowitz et al., 2017
Differentiation-associated chromatin accessibility signatures were mostly preserved during aging, indicating resilience of phenotypically defined T cell subsets.
“Differentiation-associated chromatin accessibility signatures were mostly preserved during aging, indicating the resilience of phenotypically defined T cell subsets.”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Moskowitz et al., 2017
In contrast to mouse virtual memory T cells, the age-related shift to a more differentiated state in human CD8+ T cells was incomplete and not associated with a gain in effector function, but included genes relevant to T cell proliferation.
“In contrast to virtual memory T cells in the mouse, this shift to a more differentiated state was incomplete and not associated with a gain in effector function, but included genes relevant to T cell proliferation.”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Moskowitz et al., 2017
Epigenetic differences were more discriminatory and robust than gene expression differences.
“Epigenetic differences were more discriminatory and robust than gene expression differences.”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Moskowitz et al., 2017
Naive CD8+ T cells from elderly individuals had an epigenetic profile more similar to that of young central memory T cells.
“However, naive CD8+ T cells from elderly individuals exhibited an epigenetic profile more similar to that of young central memory T cells”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Moskowitz et al., 2017
Epigenetic studies of human naive and central memory CD8+ T cells revealed an age-associated loss of chromatin accessibility at key promoters, in particular at NRF1 binding sites.
“Epigenetic studies of human naive and central memory CD8+ T cells revealed an age-associated loss of chromatin accessibility at key promoters, in particular at NRF1 binding sites”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Moskowitz et al., 2017
CD8+CD45RO+CCR7− effector memory T cells from older individuals show only few differences in chromatin accessibility compared to young effector memory T cells, and they lack epigenetic signatures of exhausted T cells.
“However, CD8+CD45RO+CCR7− effector memory T cells from older individuals show only few differences in terms of chromatin accessibility compared to young effector memory T cells, and they lack the epigenetic signatures of exhausted T cells”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Moskowitz et al., 2017
Chromatin accessibility studies in ageing immune cells have demonstrated shifts in chromatin accessibility with age in CD8+ T cells.
“Chromatin accessibility studies in ageing immune cells have demonstrated shifts in chromatin accessibility with age in CD8+ T cells144–147.”
From Measuring biological age using omics data (2022) · cites this paper as [144]
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Cites
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“RESULTS Genome-wide mapping of chromatin accessibility in CD8 T cell subsets Using the assay for transposase-accessible chromatin using sequencing (ATAC-seq) (16, 17), we generated genome-wide maps of chromatin accessibility in three human CD8 T cell subsets, purified by sorting peripheral blood mononuclear cells (PBM…”
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“RESULTS Genome-wide mapping of chromatin accessibility in CD8 T cell subsets Using the assay for transposase-accessible chromatin using sequencing (ATAC-seq) (16, 17), we generated genome-wide maps of chromatin accessibility in three human CD8 T cell subsets, purified by sorting peripheral blood mononuclear cells (PBM…”
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“We evaluated this hypothesis using published TF target sets from knockdown experiments in human-derived cell lines (25, 32).”
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“We evaluated this hypothesis using published TF target sets from knockdown experiments in human-derived cell lines (25, 32).”
MethodDefective activation and survival of T cells lacking the Ets-1 transcription factor
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Human memory T cells with a naive phenotype accumulate with aging and respond to persistent viruses
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Bach2 maintains T cells in a naive state by suppressing effector memory-related genes
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“The only bZIP TF more expressed in naïve cells than effector cells was Bach2, which is known to suppress effector-related genes to maintain a naïve state (26); this TF also shares strong motif similarity with other bZIP TFs.”
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Self-citationDerivation and Maintenance of Virtual Memory CD8 T Cells
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“We did observe minor enrichment for the binding motifs of T-bet and Eomes, which are known to be more expressed in EM than CM populations (29).”
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“Correspondingly, immune competency erodes with age, leading to higher incidences of malignancies and increased morbidity and mortality from infections (1, 2).”
BackgroundInducible chromatin priming is associated with the establishment of immunological memory in T cells
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Human T cell development, localization, and function throughout life
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“A linear progression of differentiation for human CD8+ T cells in the order naïve—Tscm—Tcm—Tem cells was suggested by methylation analysis and chromatin accessibility (Abdelsamed et al., 2017; Moskowitz et al., 2017).”
BackgroundThe twilight of immunity: emerging concepts in aging of the immune system
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“Additionally, ATAC-seq of aging naive cells demonstrated reduced promoter accessibility, especially for the DNA methylation-sensitive transcription factor NRF1 [114].”
InfluentialImmunosenescence: molecular mechanisms and diseases
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“Basic leucine zipper ATF-like TF, which is extensively expressed in aged CD8 T cells, plays a prominent role in T-cell exhaustion differentiation.(153) Terminally exhausted T cells typically exhibit upregulation of chromatin accessibility at the promoters of effector genes associated with granzyme B (GZMB) and interfe…”
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“Transcriptional activation or repression has been shown to be tightly linked with disruption or occupancy of nucleosomes at regulatory regions including promoters, enhancers, silencers, and insulators (Moskowitz et al., 2017; Shivaswamy et al., 2008).”
BackgroundSexual-dimorphism in human immune system aging
Márquez, E. J., Chung, C.-H., Marches, R., Rossi, R. J., Nehar-Belaid, D., Eroglu, A., Mellert, D. J., Kuchel, G. A., Banchereau, J., & Ucar, D. (2020) · Nature Communications · doi:10.1038/s41467-020-14396-9 · Cited by 584 · see citing works
Measuring biological age using omics data
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“Chromatin accessibility studies in ageing immune cells have demonstrated shifts in chromatin accessibility with age in CD8 + T cells 144–147 .”
BackgroundMechanisms underlying T cell ageing
Goronzy, J. J., & Weyand, C. M. (2019) · Nature Reviews Immunology · doi:10.1038/s41577-019-0180-1 · Cited by 506 · see citing works
Self-citationEpigenetic control of CD8+ T cell differentiation
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Successful and Maladaptive T Cell Aging
Goronzy, J. J., & Weyand, C. M. (2017) · Immunity · doi:10.1016/j.immuni.2017.03.010 · Cited by 362 · see citing works
“Epigenetic studies of human naive and central memory CD8+ T cells revealed an age-associated loss of chromatin accessibility at key promoters, in particular at NRF1 binding sites (Moskowitz et al., 2017).”
InfluentialSelf-citationBenayoun, B. A., Pollina, E. A., Singh, P. P., Mahmoudi, S., Harel, I., Casey, K. M., Dulken, B. W., Kundaje, A., & Brunet, A. (2019) · Genome Research · doi:10.1101/gr.240093.118 · Cited by 360 · see citing works
Single-cell chromatin modification profiling reveals increased epigenetic variations with aging
Cheung, P., Vallania, F., Warsinske, H. C., Donato, M., Schaffert, S., Chang, S. E., Dvorak, M., Dekker, C. L., Davis, M. M., Utz, P. J., et al. (2018) · Cell · doi:10.1016/j.cell.2018.03.079 · Cited by 323 · see citing works
“Recent reports have found substantial chromatin changes as a result of aging (Moskowitz et al., 2017; Ucar et al., 2017).”
Influence of immune aging on vaccine responses
Gustafson, C. E., Kim, C., Weyand, C. M., & Goronzy, J. J. (2020) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2020.03.017 · Cited by 286 · see citing works
“Consistently, recent studies reveal that naive CD8 T cells not only have decreased survival with age but that they also become phenotypically and functionally distinct from naive T cells in young adults —becoming more epigenetically, transcriptionally, and posttranscriptionally (ie, microRNA [miR]) similar to central…”
Self-citationLandscape of stimulation-responsive chromatin across diverse human immune cells
Calderon, D., Nguyen, M. L. T., Mezger, A., Kathiria, A. S., Müller, F., Nguyen, V. Q., Lescano, N., Wu, B., Trombetta, J. J., Ribado, J. V., et al. (2019) · Nature Genetics · doi:10.1038/s41588-019-0505-9 · Cited by 282 · see citing works
“4b) 20 .”
Self-citationMarkers of T Cell Senescence in Humans
Xu, W., & Larbi, A. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18081742 · Cited by 261 · see citing works
“On the epigenetic level, CD4 and CD8 T cells have been shown to have an overall decrease in methylation as they progressed from Naïve to TE [103,104].”
BackgroundThe full spectrum of human naive T cells
van den Broek, T., Borghans, J. A. M., & van Wijk, F. (2018) · Nature reviews. Immunology · doi:10.1038/s41577-018-0001-y · Cited by 258 · 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
“Thus, the memory T lymphocytes in elderly individuals do not exhibit the epigenetic marks of the exhausted T lymphocytes (124, 127).”
BackgroundPeripheral immune system in aging and Alzheimer’s disease
Cao, W., & Zheng, H. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0284-2 · Cited by 214 · see citing works
Epigenetic ageing clocks: statistical methods and emerging computational challenges
Teschendorff, A. E., & Horvath, S. (2025) · Nature Reviews Genetics · doi:10.1038/s41576-024-00807-w · Cited by 220 · see citing works
Developmental Origin Governs CD8+ T Cell Fate Decisions during Infection
Smith, N. L., Patel, R. K., Reynaldi, A., Grenier, J. K., Wang, J., Watson, N. B., Nzingha, K., Mon, K. J. Y., Peng, S. A., Grimson, A., et al. (2018) · Cell · doi:10.1016/j.cell.2018.05.029 · Cited by 204 · see citing works
The chromatin accessibility signature of human immune aging stems from CD8+ T cells
Ucar, D., Márquez, E. J., Chung, C.-H., Marches, R., Rossi, R. J., Uyar, A., Wu, T.-C., George, J., Stitzel, M. L., Palucka, A. K., et al. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20170416 · Cited by 200 · see citing works
“3, D and E) and might originate from natural killer cells (Hayhoe et al., 2010); however, multiple other cell types can express GZMB, including plasmacytoid dendritic cells (Matsui et al., 2009), CD4+ T cells (Namekawa et al., 1998; Appay et al., 2002), and plasma cells (Xu et al., 2014).”
BackgroundAge-associated remodeling of T cell immunity and metabolism
Han, S., Georgiev, P., Ringel, A. E., Sharpe, A. H., & Haigis, M. C. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.11.005 · Cited by 193 · see citing works
Clonal expansion and epigenetic inheritance of long-lasting NK cell memory
Rückert, T., Lareau, C. A., Mashreghi, M., Ludwig, L. S., & Romagnani, C. (2022) · Nature Immunology · doi:10.1038/s41590-022-01327-7 · Cited by 194 · see citing works
“Our finding of a strong enrichment of AP1 motifs in adaptive NK cell chromatin extends observations made in different cell types 4,31,39–42 , further supporting the concept of a conserved inflammatory memory signature imprinted by AP1 TFs 4,32 .”
Hallmarks of the aging T‐cell system
Zhang, H., Weyand, C. M., & Goronzy, J. J. (2021) · FEBS Journal · doi:10.1111/febs.15770 · Cited by 177 · see citing works
Self-citationAging and Neurodegenerative Disease: Is the Adaptive Immune System a Friend or Foe?
Mayne, K., White, J. A., McMurran, C. E., Rivera, F. J., & de la Fuente, A. G. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.572090 · Cited by 167 · see citing works
“…in Aging Neuroscience | www.frontiersin.org 4 September 2020 | Volume 12 | Article 572090 Mayne et al. Adaptive Immunity in Neurodegenerative Diseases Neuroinflammation in PD is a result of activated microglia and monocytes in response to misfolded protein α-synuclein (Mosley et al., 2012).”
BackgroundAging disrupts circadian gene regulation and function in macrophages
Blacher, E., Tsai, C. A., Litichevskiy, L., Shipony, Z., Iweka, C. A., Schneider, K. M., Chuluun, B., Heller, H. C., Menon, V., Thaiss, C. A., et al. (2021) · Nature Immunology · doi:10.1038/s41590-021-01083-0 · Cited by 164 · see citing works
Metabolic programs tailor T cell immunity in viral infection, cancer, and aging
Møller, S. H., Hsueh, P., Yu, Y.-R., Zhang, L., & Ho, P. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.02.003 · Cited by 148 · see citing works
Epigenetic mechanisms regulating T-cell responses
Schmidl, C., Delacher, M., Huehn, J., & Feuerer, M. (2018) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2018.07.014 · Cited by 144 · see citing works
New Insights into the Role of Histone Changes in Aging
Yi, S.-J., & Kim, K. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218241 · Cited by 132 · see citing works
Papavassiliou, A. G., & Musti, A. M. (2020) · Cells · doi:10.3390/cells9112470 · Cited by 122 · see citing works
“In line with this hypothesis, recent studies, using ATAC-seq scanning of TF-binding motifs within accessible chromatin regions, have shown that binding sites for T-bet, BATF and AP-1 are depleted in naive CD8 T cells, but enriched in effector CD8 T cells [2,19,20].”
BackgroundResultPhysiology and pathology of T-cell aging
Minato, N., Hattori, M., & Hamazaki, Y. (2020) · International Immunology · doi:10.1093/intimm/dxaa006 · Cited by 121 · see citing works
Kim, C., Hu, B., Jadhav, R. R., Jin, J., Zhang, H., Cavanagh, M., Akondy, R. S., Ahmed, R., Weyand, C. M., & Goronzy, J. J. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.10.074 · Cited by 123 · see citing works
“The CD8+ T cell compartment is more affected by age, both in size and composition as well as in function and chromatin structure (Briceño et al., 2016; Czesnikiewicz-Guzik et al., 2008; Moskowitz et al., 2017; Nikolich-Zugich et al., 2012).”
BackgroundSelf-citationLong-lived T follicular helper cells retain plasticity and help sustain humoral immunity
Künzli, M., Schreiner, D., Pereboom, T. C., Swarnalekha, N., Litzler, L. C., Lötscher, J., Ertuna, Y. I., Roux, J., Geier, F. M., Jakob, R. P., et al. (2020) · Science Immunology · doi:10.1126/sciimmunol.aay5552 · Cited by 113 · see citing works
Human circulating and tissue-resident memory CD8+ T cells
Buggert, M., Price, D. A., Mackay, L. K., & Betts, M. R. (2023) · Nature Immunology · doi:10.1038/s41590-023-01538-6 · Cited by 119 · see citing works
“This paradigm is supported in large part by studies of chromatin accessibility and DNA methylation 125,126 .”
The aged tumor microenvironment limits T cell control of cancer
Chen, C.-Y., Jaiswal, S., Martínez, D., Yerinde, C., Ji, K. Y., Miranda, V., Fung, M. E., Weiss, S. A., Zschummel, M., Taguchi, K., et al. (2024) · Nature Immunology · doi:10.1038/s41590-024-01828-7 · Cited by 110 · see citing works
“Aging is known to have a profound impact on the epigenome 6,25 , and so we profiled chromatin accessibility changes within young and aged CD8 + T cells both at baseline (before transfer) and in the TME (after transfer; Fig.”
Abnormal Epigenetic Regulation of Immune System during Aging
Jasiulionis, M. G. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00197 · Cited by 99 · see citing works
“A shift toward more differentiated state of chromatin openness was observed in naïve and central memory cells from older individuals, as well a loss of chromatin accessibility at gene promoters mediated in part by the loss of nuclear respiratory factor 1 (NRF1) binding in aged naïve cells (213).”
BackgroundCOVID-19 and Crosstalk With the Hallmarks of Aging
Salimi, S., & Hamlyn, J. M. (2020) · The Journals of Gerontology Series A · doi:10.1093/gerona/glaa149 · Cited by 95 · see citing works
Karakaslar, E. O., Katiyar, N., Hasham, M., Youn, A., Sharma, S., Chung, C., Marches, R., Korstanje, R., Banchereau, J., & Ucar, D. (2023) · Aging Cell · doi:10.1111/acel.13792 · Cited by 98 · see citing works
“These studies have uncovered significant age-related changes in gene expression levels in whole blood, as well as in blood-derived peripheral mononuclear cells (PBMCs) and sorted immune cells ((5-7)).”
BackgroundExtremely Differentiated T Cell Subsets Contribute to Tissue Deterioration During Aging
Soto‐Heredero, G., Heras, M. M. G. D. L., Escrig-Larena, J. I., & Mittelbrunn, M. (2023) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101721-064501 · Cited by 95 · see citing works
Zhang, H., Jadhav, R. R., Cao, W., Goronzy, I. N., Zhao, T. V., Jin, J., Ohtsuki, S., Hu, Z., Morales, J., Greenleaf, W. J., et al. (2022) · Nature Immunology · doi:10.1038/s41590-022-01369-x · Cited by 89 · see citing works
Self-citationZKSCAN3 counteracts cellular senescence by stabilizing heterochromatin
Hu, H., Ji, Q., Song, M., Ren, J., Liu, Z., Wang, Z., Liu, X., Yan, K., Hu, J., Jing, Y., et al. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa425 · Cited by 87 · see citing works
“Structurally, it has also been reported that chromatin in aged human cells shows more accessible than that in young counterparts (31,32).”
BackgroundNair, R., Somasundaram, V., Kuriakose, A., Krishn, S. R., Raben, D., Salazar, R. L., & Nair, P. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1548234 · Cited by 90 · see citing works
Distinct Age-Related Epigenetic Signatures in CD4 and CD8 T Cells
Hu, B., Jadhav, R. R., Gustafson, C. E., Saux, S. L., Ye, Z., Li, X., Tian, L., Weyand, C. M., & Goronzy, J. J. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.585168 · Cited by 83 · see citing works
“org 2 integrated and compared these data with previously generated epigenetic profiles of CD8 T cell subsets (19) and related these epigenetic data to differences in the transcriptomes of naïve CD4 and CD8 T cells.”
BackgroundResultInfluentialSelf-citationThe Transcription Factor TCF1 in T Cell Differentiation and Aging
Kim, C., Jin, J., Weyand, C. M., & Goronzy, J. J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186497 · Cited by 81 · see citing works
Self-citationGenetic regulation of gene expression and splicing during a 10-year period of human aging
Balliu, B., Durrant, M. G., de Goede, O. M., Abell, N. S., Li, X., Liu, B., Gloudemans, M. J., Cook, N. L., Smith, K. S., Knowles, D. A., et al. (2019) · Genome biology · doi:10.1186/s13059-019-1840-y · Cited by 83 · see citing works
“The 49 DE genes that overlap in the top 1000 discoveries between the three studies (Additional file 5) are enriched in gene ontology (GO) terms related to adaptive immune response pathways that have previously been implicated in aging [37], e.”
BackgroundYe, Z., Shen, Y., Jin, K., Qiu, J., Hu, B., Jadhav, R. R., Sheth, K., Weyand, C. M., & Goronzy, J. J. (2021) · Nature Communications · doi:10.1038/s41467-021-21242-z · Cited by 80 · see citing works
Self-citationLawlor, N. T., Nehar-Belaid, D., Grassmann, J. D. S., Stoeckius, M., Smibert, P., Stitzel, M. L., Pascual, V., Banchereau, J., Williams, A., & Ucar, D. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.636720 · Cited by 80 · see citing works
DNA damage, metabolism and aging in pro-inflammatory T cells
Li, Y., Goronzy, J. J., & Weyand, C. M. (2017) · Experimental Gerontology · doi:10.1016/j.exger.2017.10.027 · Cited by 79 · see citing works
“…progressive T cell differentiation and persistent stimulation by infectious agents will eventually build a T cell compartment with contracted diversity, partial cellular differentiation and reduced cellular competence (Czesnikiewicz-Guzik et al., 2008; Moskowitz et al., 2017; Sauce et al., 2012).”
Self-citationEpigenomic drivers of immune dysfunction in aging
Keenan, C. R., & Allan, R. S. (2018) · Aging Cell · doi:10.1111/acel.12878 · Cited by 76 · see citing works
“One study found that naïve and central memory CD8+ T cells from older humans showed a loss of chromatin accessibility at gene promoters targeted by the transcription factor NRF1 (Moskowitz et al., 2017), which regulates expression of mitochondrial respiratory chain genes, a plausible although not conclusively proven e…”
BackgroundInfluentialRegulation of miR-181a expression in T cell aging
Ye, Z., Li, G., Kim, C., Hu, B., Jadhav, R. R., Weyand, C. M., & Goronzy, J. J. (2018) · Nature Communications · doi:10.1038/s41467-018-05552-3 · Cited by 77 · see citing works
Self-citationConstrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients
Le Coz, C., Nguyen, D. N., Su, C., Nolan, B. E., Albrecht, A. V., Xhani, S., Sun, D., Demaree, B., Pillarisetti, P., Khanna, C., et al. (2021) · Journal of Experimental Medicine · doi:10.1084/jem.20201750 · Cited by 69 · see citing works
“A 50% LOESS regression on the normalized expression FCs was used to smooth gene expression over chromatin openness changes (Moskowitz et al., 2017).”
MethodMapping of γ/δ T cells Reveals Vδ2 T cells Resistance to Senescence
Xu, W., Monaco, G., Wong, E., Tan, W. L. W., Kared, H., Simoni, Y., Tan, S. W., How, W., Tan, C. T. Y., Lee, B. T. K., et al. (2018) · EBioMedicine · doi:10.1016/j.ebiom.2018.11.053 · Cited by 75 · see citing works
“Using the RRBS (Reduced Representation Bisulfite Sequencing) approach, we observed in general, a decrease in methylation as CD4 αβ T cells and CD8 αβ T cells differentiates from naïve to TE, which has been recently described even though they used a different approach for their epigenetic analysis [43,44] (Fig.”
MethodInnate and Adaptive Immunity in Giant Cell Arteritis
Akiyama, M., Ohtsuki, S., Berry, G. J., Liang, D. H., Goronzy, J. J., & Weyand, C. M. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.621098 · Cited by 73 · see citing works
“CD8 T cells are well-known to age faster than CD4 T cells and a hallmark of T cell aging is the loss of naïve CD8 T cells (93).”
BackgroundSelf-citationPatrick, R., Naval-Sánchez, M., Deshpande, N., Huang, Y., Zhang, J., Chen, X., Yang, Y., Tiwari, K., Esmaeili, M., Tran, M., et al. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.06.006 · Cited by 73 · see citing works
Márquez, E. J., Trowbridge, J. J., Kuchel, G. A., Banchereau, J., & Ucar, D. (2020) · Immunity & Ageing · doi:10.1186/s12979-020-00183-z · Cited by 71 · see citing works
The effects of age and systemic metabolism on anti-tumor T cell responses
Drijvers, J. M., Sharpe, A. H., & Haigis, M. C. (2020) · eLife · doi:10.7554/elife.62420 · Cited by 69 · see citing works
Rivas, J. R., Liu, Y., Alhakeem, S. S., Eckenrode, J. M., Martí, F., Collard, J. P., Zhang, Y., Shaaban, K. A., Muthusamy, N., Hildebrandt, G. C., et al. (2021) · Leukemia · doi:10.1038/s41375-021-01217-1 · Cited by 66 · see citing works
“17 but not in activated CD8+ T-cell subsets(48, 49).”
BackgroundAging, cancer, and antitumor immunity
Ikeda, H., & Togashi, Y. (2021) · International Journal of Clinical Oncology · doi:10.1007/s10147-021-01913-z · Cited by 65 · see citing works
Luo, Q., Dwaraka, V. B., Chen, Q., Tong, H., Zhu, T., Seale, K., Raffaele, J. M., Zheng, S., Mendez, T. L., Chen, Y., et al. (2023) · Genome Medicine · doi:10.1186/s13073-023-01211-5 · Cited by 61 · see citing works
Heterogeneity and transcriptome changes of human CD8+ T cells across nine decades of life
Lü, J., Ahmad, R., Nguyen, T. B. V., Cifello, J., Hemani, H., Li, J., Chen, J., Li, S., Wang, J., Achour, A., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-32869-x · Cited by 61 · see citing works
Transcription factor networks in aged naïve CD4 T cells bias lineage differentiation
Hu, B., Li, G., Ye, Z., Gustafson, C. E., Tian, L., Weyand, C. M., & Goronzy, J. J. (2019) · Aging Cell · doi:10.1111/acel.12957 · Cited by 60 · see citing works
“Most importantly, we found BATF to be overexpressed, reminiscent to our previous finding in CD8 T cells that increased accessibility to BATF‐binding motifs is an epigenetic hallmark of T‐cell aging (Moskowitz et al., 2017).”
BackgroundSelf-citationDNA methylation clocks for estimating biological age in Chinese cohorts
Zheng, Z., Li, J., Liu, T., Fan, Y., Zhai, Q., Xiong, M., Wang, Q., Sun, X., Zheng, Q.-W., Che, S., et al. (2024) · Protein & Cell · doi:10.1093/procel/pwae011 · Cited by 63 · see citing works
“…loss of nuclear respiratory factor 1 (NRF1), a key regulator in proteostasis maintenance (Cui et al., 2021; Lehrbach and Ruvkun, 2019), is thought to contribute to aging especially in naïve T cells, causing loss of chromatin accessibility at gene promoters (Moskowitz et al., 2017a, 2017b).”
BackgroundSIRT6 Widely Regulates Aging, Immunity, and Cancer
Li, Y., Jin, J., & Wang, Y. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.861334 · Cited by 59 · see citing works
“Subsequently, researchers found that the central memory cells of older individuals shifted toward a chromatinopening pattern and determined that the gene regulation driven by NRF1 and BATF was a potential target for delaying CD8 T cell aging (87).”
BackgroundATAC-clock: An aging clock based on chromatin accessibility
Morandini, F., Rechsteiner, C., Pérez, K., Praz, V., Garcia, G. L., Hinte, L. C., von Meyenn, F., & Ocampo, A. (2023) · GeroScience · doi:10.1007/s11357-023-00986-0 · Cited by 60 · see citing works
“Previous studies have observed age-related changes in chromatin accessibility in multiple organisms [20–23].”
Goronzy, J. J., Hu, B., Kim, C., Jadhav, R. R., & Weyand, C. M. (2018) · Journal of Leukocyte Biology · doi:10.1002/jlb.1ri0418-160r · Cited by 60 · see citing works
Self-citationMitochondria during T cell aging
Escrig-Larena, J. I., Delgado-Pulido, S., & Mittelbrunn, M. (2023) · Seminars in Immunology · doi:10.1016/j.smim.2023.101808 · Cited by 58 · see citing works
Quinn, K. M., Hussain, T., Kraus, F., Formosa, L. E., Lam, W. K., Dagley, M. J., Saunders, E. C., Assmus, L. M., Wynne-Jones, E., Loh, L., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16633-7 · Cited by 56 · see citing works
Immunosenescence and Altered Vaccine Efficiency in Older Subjects: A Myth Difficult to Change
Fülöp, T., Larbi, A., Pawelec, G., Cohen, A. A., Provost, G., Khalil, A., Lacombe, G., Rodrigues, S., Desroches, M., Hirokawa, K., et al. (2022) · Vaccines · doi:10.3390/vaccines10040607 · Cited by 56 · see citing works
“The successive differentiations induce telomere shortening contributing but are not sufficient to induce cell senescence [87, 117,118].”
BackgroundTan, J., Liang, Y., Zhou, Y., He, Q., Tong, J., Deng, Y., Guo, W., Liang, K., Tang, J., Shi, W., et al. (2023) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.123.318974 · Cited by 55 · see citing works
“As a transcription factor, ETS1 has been shown to be related to the differentiation and activation of T cells 65,66 with its role in atherosclerosis never reported.”
BackgroundCytokines, growth factors and proteases in medium and large vessel vasculitis
Weyand, C. M., Watanabe, R., Zhang, H., Akiyama, M., Berry, G. J., & Goronzy, J. J. (2019) · Clinical Immunology · doi:10.1016/j.clim.2019.02.007 · Cited by 53 · see citing works
“CD8 T cells are known to age faster than CD4 T cells and a hallmark of immune aging is the loss of naïve CD8 T cells [60], suggesting acceleration of T cell aging in GCA with direct pathogenic relevance.”
BackgroundSelf-citationThe clock is ticking: the impact of ageing on T cell metabolism
Quinn, K. M., Palchaudhuri, R., Palmer, C. S., & Gruta, N. L. L. (2019) · Clinical & Translational Immunology · doi:10.1002/cti2.1091 · Cited by 51 · see citing works
“With regard to na€ıve T cells, a recent study of epigenetic changes in unstimulated human naive CD8 T cells demonstrated an increase in mitochondrial mass but, somewhat counterintuitively, a loss of mitochondrial respiratory capacity in aged cells.(95) The loss of respiratory capacity appeared to be driven by diminish…”
BackgroundmiR-181a-regulated pathways in T-cell differentiation and aging
Kim, C., Ye, Z., Weyand, C. M., & Goronzy, J. J. (2021) · Immunity & Ageing · doi:10.1186/s12979-021-00240-1 · Cited by 54 · see citing works
“bility to YY1 binding sites at gene promoters [86, 87].”
BackgroundSelf-citationLiu, Q., Li, J., Sun, X., Lin, J., Yu, Z., Xiao, Y., Li, D., Sun, B., Bao, H., & Liu, Y. (2025) · Journal of Hematology & Oncology · doi:10.1186/s13045-025-01735-w · Cited by 54 · see citing works
“…T cells due to diminished NRF1 binding, culminating in impaired respiratory chain gene transcription and oxidative phosphorylation capacity, which indicates the NRF1 may be identified as a potential target for interventions aimed at decelerating CD8 + T cell senescence and restoring function [379].”
Zhou, J., So, K. K. H., Li, Y., Li, Y., Yuan, J., Ding, Y., Chen, F., Huang, Y., Liu, J., Lee, W., et al. (2019) · Aging Cell · doi:10.1111/acel.12996 · Cited by 51 · see citing works
“…of interferon‐related path‐ ways in heart, liver, cerebellum, olfactory bulb, and primary cultures of neural stem cells (NSCs) throughout mouse lifespan (Benayoun et al., 2018); Moskowitz et al. (2017) reported an increased enhancer openness, while a loss of promoter openness in aging CD8+ T cells.”
BackgroundAre immunosenescent T cells really senescent?
Slaets, H., Veeningen, N., de Keizer, P. L. J., Hellings, N., & Hendrix, S. (2024) · Aging Cell · doi:10.1111/acel.14300 · Cited by 53 · see citing works
“They found a loss of accessibility in gene promoter regions of the nuclear respiratory factor 1 (NRF1) in naïve CD8 + T cells of aged individuals (Moskowitz et al., 2017) NRF1 is a transcription factor that regulates gene expression of mitochondrial respiratory chain proteins.”
BackgroundDefects in Antiviral T Cell Responses Inflicted by Aging-Associated miR-181a Deficiency
Kim, C., Jadhav, R. R., Gustafson, C. E., Smithey, M. J., Hirsch, A. J., Uhrlaub, J. L., Hildebrand, W. H., Nikolich‐Žugich, J., Weyand, C. M., & Goronzy, J. J. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.10.044 · Cited by 47 · see citing works
Self-citationFunctional pathways regulated by microRNA networks in CD8 T‐cell aging
Gustafson, C. E., Cavanagh, M., Jin, J., Weyand, C. M., & Goronzy, J. J. (2018) · Aging Cell · doi:10.1111/acel.12879 · Cited by 45 · see citing works
Self-citationImmune Memory in Aging: a Wide Perspective Covering Microbiota, Brain, Metabolism, and Epigenetics
Bulut, O. P., Kılıç, G., & Domínguez‐Andrés, J. (2021) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-021-08905-x · Cited by 48 · see citing works
T-Cell Aging-Associated Phenotypes in Autoimmune Disease
Zhao, T. V., Sato, Y., Goronzy, J. J., & Weyand, C. M. (2022) · Frontiers in Aging · doi:10.3389/fragi.2022.867950 · Cited by 50 · see citing works
“…from persistent activation of the mTOR pathway (Kim et al., 2018; Wen et al., 2019; Jin J. et al., 2021), hypersensitivity to activating stimuli surrounding the cells and global restructuring of DNA accessibility and histone synthesis and modification (Moskowitz et al., 2017; Kim et al., 2021).”
BackgroundSelf-citationThomson, Z., He, Z., Swanson, E. G., Henderson, K., Phalen, C. G., Zaim, S. R., Pebworth, M.-P., Okada, L. Y., Heubeck, A. T., Roll, C. R., et al. (2023) · Nature Immunology · doi:10.1038/s41590-023-01641-8 · Cited by 43 · see citing works
“Studies have demonstrated that the naive CD8 + T cell compartment is also affected by naive-like memory cell infiltration 2–4 and pseudodifferentiation toward memory-like epigenetic programming that biases naive CD8 + T cell development into effector phenotypes 5,6 .”
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“In particular, aging CD8+ T cells lose chromatin accessibility at promoters, which may compromise their metabolic state [14].”
BackgroundImmunosenescence and inflammaging: Mechanisms and modulation through diet and lifestyle
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“Epigenetic drift, involving alterations in DNA methylation and histone modi fi cations, reshapes the transcriptional landscape of immune cells and affects their differentiation and activation potential (34).”
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“Old naïve CD8 + T cells failed to transcribe respiratory chain genes, causing a collapse in mitochondrial function, specifically in oxidative phosphorylation [155].”
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“Chromatin accessibility analysis of aged CD8+ T-cells from human donors revealed a decrease in promoter accessibility (Moskowitz et al, 2017; Ucar et al, 2017).”
BackgroundNuclear Sirtuins and the Aging of the Immune System
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“Subsequent epigenetic studies mapping chromatin accessibility in T cells stratified for CD4 and CD8 naïve, central and effector memory cells identified differentially accessible sites that included motifs for transcription factors associated with effector cell differentiation (34).”
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“Genome-wide studies reveal unique gene expression profiles among different CD8þ T-cell subsets (11, 37).”
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“Thus, it has become a popular tool in epigenomics research and can be used in population-level epigenome studies [103].”
MethodTRIB2 safeguards naive T cell homeostasis during aging
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Premature aging of circulating T cells predicts all-cause mortality in hemodialysis patients
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“This is partly explained by some epigenetic studies [15, 16].”
Background
- Authors
- Moskowitz, D. M., Zhang, D. W., Hu, B., Le Saux, S., Yanes, R. E., Ye, Z., Buenrostro, J. D., Weyand, C. M., Greenleaf, W. J., & Goronzy, J. J.
- Affiliations
- Stanford Medicine (US)
- VA Palo Alto Health Care System (US)
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
- Howard Hughes Medical Institute (US)
- Corresponding author
- Moskowitz, David M.
- Zhang, David W.
- Greenleaf, William J.
- Goronzy, Jörg J.
- ORCID
- Venue
- Science Immunology
- Published
- 2017-02-24
- Volume
- 2
- Issue
- 8
- ISSN
- 2470-9468 (ISSN-L)
- PMC
- PMC5399889
- OpenAlex
- W2587865057
- Cited by
- 252
- References
- 53
- Citations by year
- 2026: 23 · 2025: 28 · 2024: 30 · 2023: 29 · 2022: 30 · 2021: 28 · 2020: 26 · 2019: 21 · 2018: 29 · 2017: 8
- FWCI
- 10.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (award297003, R01 AI108891, R01 AG015043, U19 AI057266, P50HG007735)
- Rita Allen Foundation (award297004)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- immunosenescence, T cell differentiation, chromatin accessibility, transcription factor binding, naive T cells, central memory T cells, effector memory T cells, BATF, NRF1, ETS1, Eomes, Sp1, oxidative phosphorylation, transcriptional regulatory networks
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