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Obesity accelerates T cell senescence in murine visceral adipose tissue
Open accessAbstract
Chronic inflammation in visceral adipose tissue (VAT) precipitates the development of cardiometabolic disorders. Although changes in T cell function associated with visceral obesity are thought to affect chronic VAT inflammation, the specific features of these changes remain elusive. Here, we have determined that a high-fat diet (HFD) caused a preferential increase and accumulation of CD44hiCD62LloCD4+ T cells that constitutively express PD-1 and CD153 in a B cell-dependent manner in VAT. These cells possessed characteristics of cellular senescence and showed a strong activation of Spp1 (encoding osteopontin [OPN]) in VAT. Upon T cell receptor stimulation, these T cells also produced large amounts of OPN in a PD-1-resistant manner in vitro. The features of CD153+PD-1+CD44hiCD4+ T cells were highly reminiscent of senescence-associated CD4+ T cells that normally increase with age. Adoptive transfer of CD153+PD-1+CD44hiCD4+ T cells from HFD-fed WT, but not Spp1-deficient, mice into the VAT of lean mice fed a normal diet recapitulated the essential features of VAT inflammation and insulin resistance. Our results demonstrate that a distinct CD153+PD-1+CD44hiCD4+ T cell population that accumulates in the VAT of HFD-fed obese mice causes VAT inflammation by producing large amounts of OPN. This finding suggests a link between visceral adiposity and immune aging.
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“TNSF8+PDCD1+CD44hiCD4+ (CD153+PDCD+CD44hiCD4+) T cells accumulate in adipose tissue in obesity and show senescence features, including increased expression of SPP1, CDKN2A and CDKN1A and decreased expression of SATB1, DUSP10 and EEF1A1128.”
From SenNet recommendations for detecting senescent cells in different tissues (2024) · cites this paper as [128]
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Shimi, G., Sohouli, M. H., Ghorbani, A., Shakery, A., & Zand, H. (2024) · Immunity & Ageing · doi:10.1186/s12979-024-00414-7 · Cited by 79
“A study on mice fed a high-fat diet (HFD) also demonstrated the accumulation and increase of senescence-associated immune cells in visceral adipose tissue (VAT) [23].”
BackgroundInfluentialLeukocyte Heterogeneity in Adipose Tissue, Including in Obesity
Weinstock, A., Silva, H. M., Moore, K. J., Schmidt, A. M., & Fisher, E. A. A. (2020) · Circulation Research · doi:10.1161/circresaha.120.316203 · Cited by 68
The interplay of obesity, gut microbiome and diet in the immune check point inhibitors therapy era
Spyrou, N., Vallianou, N. G., Kadillari, J., & Dalamaga, Μ. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.05.008 · Cited by 66
Targeting aging and age-related diseases with vaccines
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“In a seminal work, a distinct subset of senescent T cells (CD4 + CD44 hi CD62L lo PD-1 + CD153 + ) was found to accumulate in adipose tissues, aggravating local and systemic inflammatory responses 164 .”
Adipose tissue, immune aging, and cellular senescence
Frasca, D., & Blomberg, B. B. (2020) · Seminars in Immunopathology · doi:10.1007/s00281-020-00812-1 · Cited by 72
The cGAS–STING pathway: more than fighting against viruses and cancer
Bao, T., Liu, J., Leng, J., & Cai, L. (2021) · Cell & Bioscience · doi:10.1186/s13578-021-00724-z · Cited by 64
Senescent stromal cells: roles in the tumor microenvironment
Gabai, Y., Assouline, B., & Ben‐Porath, I. (2022) · Trends in cancer · doi:10.1016/j.trecan.2022.09.002 · Cited by 67
HIV Persistence in Adipose Tissue Reservoirs
Couturier, J. P., & Lewis, D. E. (2018) · Current HIV/AIDS Reports · doi:10.1007/s11904-018-0378-z · Cited by 66
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In vivo analysis of γH2AX+ cells in skeletal muscle from aged and obese humans
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“72 In satellite cells isolated from young (15-24) and old (72-80) humans, the rate of division, maximum number of divisions, p16 mRNA, and telomere length are not different.”
BackgroundThe role of immune dysfunction in obesity-associated cancer risk, progression, and metastasis
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Collagens Regulating Adipose Tissue Formation and Functions
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T Cells in Adipose Tissue in Aging
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“Compared to CD4+ T cells, CD8+ T cells show a greater increase in adipose tissue in obesity and in aging (31, 43, 106).”
BackgroundThe Dual Role of the Pervasive “Fattish” Tissue Remodeling With Age
Conte, M., Martucci, M., Sandri, M., Franceschi, C., & Salvioli, S. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00114 · Cited by 58
“In WAT, there are different types of immune cells that under stress conditions, such as obesity, impair their immune capacity increasing the pro-inflammatory behaviors in adipose tissue (89).”
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“large numbers in visceral fat tissues of mice fed a high-fat diet and cause visceral adiposity with increased insulin resistance (16).”
BackgroundSelf-citationInnate PD-L1 limits T cell–mediated adipose tissue inflammation and ameliorates diet-induced obesity
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“As previously reported (28, 33), adipose tissue CD4+ T cells and ILC2s expressed high amounts of PD-1 (Fig.”
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The role of adipokines in systemic sclerosis: a missing link?
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“Numerous studies have also linked diabetes (and obesity) to dysregulation of the inflammatory response by upregulation of Th1 and Th2 cells and induced dysfunction of Th17 and Treg cells [108, 110-112].”
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“Previous reports showed that CD153 + PD1 + CD4 + T cells express a cellular senescence signature and secrete pro-inflammatory cytokines, including OPN, 39 a known SASP factor 49 and profibrotic molecule upregulated by IL-6 trans-signaling 50 that regulates epithelial-mesenchymal transition 51 and is expressed in vario…”
BackgroundAdipose tissue immune cells in obesity, type 2 diabetes mellitus and cardiovascular diseases
Cinkajzlová, A., Mráz, M., & Haluzík, M. (2021) · Journal of Endocrinology · doi:10.1530/joe-21-0159 · Cited by 47
The role of cellular senescence in aging through the prism of Koch-like criteria
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T-Cell Senescence in Human Metabolic Diseases
Nga, H. T., Nguyen, T. L., & Yi, H. (2024) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2024.0140 · Cited by 47
“This was accompanied by an increase in the expression of several markers, including SA-β-Gal, phosphorylation of H2A histone family member X (H2AX) (γ-H2AX), as well as cyclin-dependent kinase inhibitor 1A (Cdkn1a)/Cdkn2b [59].”
BackgroundDistinct adipose progenitor cells emerging with age drive active adipogenesis
Wang, G., Li, G., Song, A., Zhao, Y., Yu, J., Wang, Y., Dai, W., Salas, M. C., Qin, H., Medrano, L. J., et al. (2025) · Science · doi:10.1126/science.adj0430 · Cited by 47
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Terminally Differentiated CD4+ T Cells Promote Myocardial Inflammaging
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“Despite presenting defective TCR-mediated proliferation, SA-T cell stimulation has been reported to result in abundant production of TNF, IL-6, and osteopontin (47).”
BackgroundRecent Advances in Aging and Immunosenescence: Mechanisms and Therapeutic Strategies
Wang, S., Huo, T., Lu, M., Zhao, Y., Zhang, J., He, W., & Chen, H. (2025) · Cells · doi:10.3390/cells14070499 · Cited by 47
“Senescent T cells, which increase with age, are defined as CD4 + CD44 high CD62L low PD-1 + CD153 + cells and accumulate in the visceral adipose tissue (VAT) of obese individuals, directly correlating with the development of various diseases [99].”
The AI-Assisted Identification and Clinical Efficacy of Baricitinib in the Treatment of COVID-19
Richardson, P. J., Robinson, B. W. S., Smith, D. P., & Stebbing, J. (2022) · Vaccines · doi:10.3390/vaccines10060951 · Cited by 44
“In rodent models, senescent T cells can induce diabetes and obesity, while their clearance moderates the disease [13,14].”
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Metadata
- Authors
- Shirakawa, K., Yan, X., Shinmura, K., Endo, J., Kataoka, M., Katsumata, Y., Yamamoto, T., Anzai, A., Isobe, S., Yoshida, N., Itoh, H., Manabe, I., Sekai, M., Hamazaki, Y., Fukuda, K., Minato, N., & Sano, M.
- Affiliations
- Keio University (JP)
- Shanghai Jiao Tong University (CN)
- Hyogo Medical University (JP)
- The University of Tokyo (JP)
- Kyoto University (JP)
- Corresponding author
- Minato, Nagahiro
- Sano, Motoaki
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2016-11-07
- Volume
- 126
- Issue
- 12
- Pages
- 4626-4639
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC5127667
- OpenAlex
- W2548313353
- Cited by
- 271
- References
- 54
- Citations by year
- 2026: 8 · 2025: 22 · 2024: 30 · 2023: 34 · 2022: 31 · 2021: 43 · 2020: 28 · 2019: 24 · 2018: 32 · 2017: 16
- FWCI
- 22.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Keio University
- Japan Foundation for Aging and Health
- National Institutes of Health
- Japan Society for the Promotion of Science (15H01160, 22590814, 24111008, 15H04825, 24111001, 15K19125)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- visceral obesity, T cell senescence, visceral adipose tissue inflammation, osteopontin, PD-1, CD4+ T cells, high-fat diet, immunosenescence, insulin resistance, CD44, L-selectin, adoptive transfer
- MeSH terms
- Animals, B-Lymphocytes, Dietary Fats, Inflammation, Obesity, Receptors, Antigen, T-Cell, CD4-Positive T-Lymphocytes, Antigens, CD, Cellular Senescence, Mice, Knockout, Intra-Abdominal Fat, Mice, Osteopontin
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