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Cited by 43Cardiac Fibrosis and RemodelingAtherosclerosis and Cardiovascular DiseasesT-cell and B-cell Immunology

Terminally Differentiated CD4+ T Cells Promote Myocardial Inflammaging

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Delgobo, Murilo, Heinrichs, Margarete, Hapke, Nils, Ashour, DiyaaElDin, Appel, Marc, Srivastava, Mugdha, Heckel, Tobias, Spyridopoulos, Ioakim +3 more·2021·Frontiers in Immunology
DOI 10.3389/fimmu.2021.584538PMC PMC7935504
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Abstract

The cardiovascular and immune systems undergo profound and intertwined alterations with aging. Recent studies have reported that an accumulation of memory and terminally differentiated T cells in elderly subjects can fuel myocardial aging and boost the progression of heart diseases. Nevertheless, it remains unclear whether the immunological senescence profile is sufficient to cause age-related cardiac deterioration or merely acts as an amplifier of previous tissue-intrinsic damage. Herein, we sought to decompose the causality in this cardio-immune crosstalk by studying young mice harboring a senescent-like expanded CD4+ T cell compartment. Thus, immunodeficient NSG-DR1 mice expressing HLA-DRB1*01:01 were transplanted with human CD4+ T cells purified from matching donors that rapidly engrafted and expanded in the recipients without causing xenograft reactions. In the donor subjects, the CD4+ T cell compartment was primarily composed of naïve cells defined as CCR7+CD45RO-. However, when transplanted into young lymphocyte-deficient mice, CD4+ T cells underwent homeostatic expansion, upregulated expression of PD-1 receptor and strongly shifted towards effector/memory (CCR7- CD45RO+) and terminally-differentiated phenotypes (CCR7-CD45RO-), as typically seen in elderly. Differentiated CD4+ T cells also infiltrated the myocardium of recipient mice at comparable levels to what is observed during physiological aging. In addition, young mice harboring an expanded CD4+ T cell compartment showed increased numbers of infiltrating monocytes, macrophages and dendritic cells in the heart. Bulk mRNA sequencing analyses further confirmed that expanding T-cells promote myocardial inflammaging, marked by a distinct age-related transcriptomic signature. Altogether, these data indicate that exaggerated CD4+ T-cell expansion and differentiation, a hallmark of the aging immune system, is sufficient to promote myocardial alterations compatible with inflammaging in juvenile healthy mice.

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  • Accumulation of activated memory cardiac T cells in the mediastinal lymph node and myocardium is associated with myocardial aging, leading to significantly lower cardiac output.

    “Another investigation demonstrated that the accumulation of activated memory cardiac T cells in the mediastinal lymph node and myocardium is associated with myocardial aging, leading to significantly lower cardiac output. 271,300,301”

    From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [301]

    The Results (page not provided) report effector-memory CD4+ T cells infiltrating the myocardium, and the Discussion links T-cell changes to myocardial aging. The Discussion mentions enrichment in heart-draining lymph nodes in a previous study, but this paper does not establish the claimed accumulation in mediastinal lymph nodes. It also says the authors observed no functional myocardial alterations in their experiment, so the claim of significantly lower cardiac output is unsupported. (LLM, conf=0.88)

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Research works printed but not linked: 45

  1. [1]Peters A Delhey K Nakagawa S Aulsebrook A Verhulst S. Immunosenescence in wild animals: meta-analysis and outlook. Ecol Lett (2019) 22(10): 1709–22. 10.1111/ele.13343 31321874 · DOI
  2. [2]Alpert A Pickman Y Leipold M Rosenberg-Hasson Y Ji X Gaujoux R. A clinically meaningful metric of immune age derived from high-dimensional longitudinal monitoring. Nat Med (2019) 25(3): 487–95. 10.1038/s41591-019-0381-y PMC6686855 30842675 · DOI · Paper page
  3. [5]Franceschi C Garagnani P Parini P Giuliani C Santoro A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol (2018) 14(10): 576–90. 10.1038/s41574-018-0059-4 30046148 · DOI · Paper page
  4. [6]Wherry EJ. T cell exhaustion. Nat Immunol (2011) 12(6): 492–9. 10.1038/ni.2035 21739672 · DOI · Paper page
  5. [7]Pawelec G Gupta S. Editorial: Immunology of Aging. Front Immunol (2019) 10: 1614. 10.3389/fimmu.2019.01614 31354744 PMC6636427 · DOI
  6. [8]Pawelec G. Immunosenenescence: role of cytomegalovirus. Exp Gerontol (2014) 54: 1– 5. 10.1016/j.exger.2013.11.010 24291068 · DOI · Paper page
  7. [9]Wikby A Maxson P Olsson J Johansson B Ferguson FG. Changes in CD8 and CD4 lymphocyte subsets, T cell proliferation responses and non-survival in the very old: the Swedish longitudinal OCTO-immune study. Mech Ageing Dev (1998) 102(2-3): 187–98. 10.1016/S0047-6374(97)00151-6 9720651 · DOI
  8. [12]Spyridopoulos I Martin-Ruiz C Hilkens C Yadegarfar ME Isaacs J Jagger C. CMV seropositivity and T-cell senescence predict increased cardiovascular mortality in octogenarians: results from the Newcastle 85+ study. Aging Cell (2016) 15(2): 389–92. 10.1111/acel.12430 PMC4783336 26696322 · DOI · Paper page
  9. [13]Moro-Garcia MA Lopez-Iglesias F Marcos-Fernandez R Bueno-Garcia E Diaz-Molina B Lambert JL. More intensive CMV-infection in chronic heart failure patients contributes to higher T-lymphocyte differentiation degree. Clin Immunol (2018) 192: 20–9. 10.1016/j.clim.2018.03.015 29608971 · DOI
  10. [14]Martin-Ruiz C Hoffmann J Shmeleva E Zglinicki TV Richardson G Draganova L. CMV-independent increase in CD27-CD28+ CD8+ EMRA T cells is inversely related to mortality in octogenarians. NPJ Aging Mech Dis (2020) 6: 3. 10.1038/s41514-019-0041-y 31993214 PMC6972903 · DOI
  11. [15]Shultz LD Lyons BL Burzenski LM Gott B Chen X Chaleff S. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J Immunol (2005) 174(10): 6477–89. 10.4049/jimmunol.174.10.6477 15879151 · DOI
  12. [16]Gil-Cruz C Perez-Shibayama C De Martin A Ronchi F van der Borght K Niederer R. Microbiota-derived peptide mimics drive lethal inflammatory cardiomyopathy. Science (2019) 366(6467): 881–6. 10.1126/science.aav3487 31727837 · DOI · Paper page
  13. [17]Kluin RJC Kemper K Kuilman T de Ruiter JR Iyer V Forment JV. XenofilteR: computational deconvolution of mouse and human reads in tumor xenograft sequence data. BMC Bioinf (2018) 19(1): 366. 10.1186/s12859-018-2353-5 PMC6172735 30286710 · DOI
  14. [18]Reimand J Kull M Peterson H Hansen J Vilo J. g:Profiler–a web-based toolset for functional profiling of gene lists from large-scale experiments. Nucleic Acids Res (2007) 35(Web Server issue): W193–200. 10.1093/nar/gkm226 PMC1933153 17478515 · DOI
  15. [21]Rieckmann M Delgobo M Gaal C Buchner L Steinau P Reshef D. Myocardial infarction triggers cardioprotective antigen-specific T helper cell responses. J Clin Invest (2019) 129(11): 4922–36. 10.1172/JCI123859 PMC6819128 31408441 · DOI
  16. [23]Jameson SC Masopust D. Understanding Subset Diversity in T Cell Memory. Immunity (2018) 48(2): 214–26. 10.1016/j.immuni.2018.02.010 PMC5863745 29466754 · DOI · Paper page
  17. [24]Zhang W Song M Qu J Liu GH. Epigenetic Modifications in Cardiovascular Aging and Diseases. Circ Res (2018) 123(7): 773–86. 10.1161/CIRCRESAHA.118.312497 30355081 · DOI
  18. [25]Field AE Robertson NA Wang T Havas A Ideker T Adams PD. DNA Methylation Clocks in Aging: Categories, Causes, and Consequences. Mol Cell (2018) 71(6): 882–95. 10.1016/j.molcel.2018.08.008 PMC6520108 30241605 · DOI
  19. [26]Kakimoto Y Okada C Kawabe N Sasaki A Tsukamoto H Nagao R. Myocardial lipofuscin accumulation in ageing and sudden cardiac death. Sci Rep (2019) 9(1): 3304. 10.1038/s41598-019-40250-0 30824797 PMC6397159 · DOI
  20. [27]Ng TP Camous X Nyunt MSZ Vasudev A Tan CTY Feng L. Markers of T-cell senescence and physical frailty: insights from Singapore Longitudinal Ageing Studies. NPJ Aging Mech Dis (2015) 1: 15005. 10.1038/npjamd.2015.5 28721254 PMC5514983 · DOI · Paper page
  21. [30]Liu W Putnam AL Xu-Yu Z Szot GL Lee MR Zhu S. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med (2006) 203(7): 1701–11. 10.1084/jem.20060772 PMC2118339 16818678 · DOI · Paper page
  22. [31]Liu J Wang DZ. An epigenetic “LINK(RNA)” to pathological cardiac hypertrophy. Cell Metab (2014) 20(4): 555–7. 10.1016/j.cmet.2014.09.011 PMC4886471 25295782 · DOI
  23. [32]Rosa M Chignon A Li Z Boulanger MC Arsenault BJ Bosse Y. A Mendelian randomization study of IL6 signaling in cardiovascular diseases, immune-related disorders and longevity. NPJ Genom Med (2019) 4: 23. 10.1038/s41525-019-0097-4 31552141 PMC6754413 · DOI
  24. [33]Peiro C Lorenzo O Carraro R Sanchez-Ferrer CF. IL-1beta Inhibition in Cardiovascular Complications Associated to Diabetes Mellitus. Front Pharmacol (2017) 8: 363. 10.3389/fphar.2017.00363 28659798 PMC5468794 · DOI
  25. [34]Yabluchanskiy A Ma Y Iyer RP Hall ME Lindsey ML. Matrix metalloproteinase-9: Many shades of function in cardiovascular disease. Physiol (Bethesda) (2013) 28(6): 391– 403. 10.1152/physiol.00029.2013 PMC3858212 24186934 · DOI
  26. [35]Horn MA Trafford AW. Aging and the cardiac collagen matrix: Novel mediators of fibrotic remodelling. J Mol Cell Cardiol (2016) 93: 175–85. 10.1016/j.yjmcc.2015.11.005 PMC4945757 26578393 · DOI
  27. [36]de Magalhaes JP Curado J Church GM. Meta-analysis of age-related gene expression profiles identifies common signatures of aging. Bioinformatics (2009) 25(7): 875–81. 10.1093/bioinformatics/btp073 PMC2732303 19189975 · DOI · Paper page
  28. [37]Croft M. The role of TNF superfamily members in T-cell function and diseases. Nat Rev Immunol (2009) 9(4): 271–85. 10.1038/nri2526 PMC2737409 19319144 · DOI
  29. [38]Yang L Xu LZ Liu ZQ Yang G Geng XR Mo LH. Interleukin-13 interferes with activation-induced t-cell apoptosis by repressing p53 expression. Cell Mol Immunol (2016) 13(5): 669–77. 10.1038/cmi.2015.50 PMC5037282 26189367 · DOI
  30. [39]Vidal R Wagner JUG Braeuning C Fischer C Patrick R Tombor L. Transcriptional heterogeneity of fibroblasts is a hallmark of the aging heart. JCI Insight (2019) 4(22). 10.1172/jci.insight.131092 PMC6948853 31723062 · DOI
  31. [41]Jaiswal S Natarajan P Silver AJ Gibson CJ Bick AG Shvartz E. Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. N Engl J Med (2017) 377(2): 111–21. 10.1056/NEJMoa1701719 PMC6717509 28636844 · DOI · Paper page
  32. [42]Dorsheimer L Assmus B Rasper T Ortmann CA Ecke A Abou-El-Ardat K. Association of Mutations Contributing to Clonal Hematopoiesis With Prognosis in Chronic Ischemic Heart Failure. JAMA Cardiol (2019) 4(1): 25– 33. 10.1001/jamacardio.2018.3965 30566180 PMC6439691 · DOI · Paper page
  33. [43]Appel M Frantz S Campos Ramos G. Myocardial inflammation comes of age. Curr Opin Physiol (2021) 19: 47– 54. 10.1016/j.cophys.2020.09.006 · DOI
  34. [44]Elyahu Y Hekselman I Eizenberg-Magar I Berner O Strominger I Schiller M. Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes. Sci Adv (2019) 5(8): eaaw8330. 10.1126/sciadv.aaw8330 31457092 PMC6703865 · DOI · Paper page
  35. [45]Panwar A Jhun M Rentsendorj A Mardiros A Cordner R Birch K. Functional recreation of age-related CD8 T cells in young mice identifies drivers of aging- and human-specific tissue pathology. Mech Ageing Dev (2020) 191: 111351. 10.1016/j.mad.2020.111351 32910956 PMC7567339 · DOI
  36. [46]Moxham VF Karegli J Phillips RE Brown KL Tapmeier TT Hangartner R. Homeostatic proliferation of lymphocytes results in augmented memory-like function and accelerated allograft rejection. J Immunol (2008) 180(6): 3910–8. 10.4049/jimmunol.180.6.3910 18322199 · DOI
  37. [50]Desdin-Mico G Soto-Heredero G Aranda JF Oller J Carrasco E Gabande-Rodriguez E. T cells with dysfunctional mitochondria induce multimorbidity and premature senescence. Science (2020) 368(6497): 1371–6. 10.1126/science.aax0860 PMC7616968 32439659 · DOI · Paper page
  38. [51]Martini E Cremonesi M Panico C Carullo P Bonfiglio CA Serio S. T Cell Costimulation Blockade Blunts Age-Related Heart Failure. Circ Res (2020) 127(8): 1115–7. 10.1161/CIRCRESAHA.119.316530 PMC7508271 32806992 · DOI
  39. [52]Lee JY Han AR Lee DR. T Lymphocyte Development and Activation in Humanized Mouse Model. Dev Reprod (2019) 23(2): 79– 92. 10.12717/DR.2019.23.2.079 31321348 PMC6635618 · DOI
  40. [53]Brehm MA Kenney LL Wiles MV Low BE Tisch RM Burzenski L. Lack of acute xenogeneic graft- versus-host disease, but retention of T-cell function following engraftment of human peripheral blood mononuclear cells in NSG mice deficient in MHC class I and II expression. FASEB J (2019) 33(3): 3137–51. 10.1096/fj.201800636R PMC6404556 30383447 · DOI
  41. [54]Satheesan S Li H Burnett JC Takahashi M Li S Wu SX. HIV Replication and Latency in a Humanized NSG Mouse Model during Suppressive Oral Combinational Antiretroviral Therapy. J Virol (2018) 92(7): e02118–17. 10.1128/JVI.02118-17 PMC5972864 29343582 · DOI
  42. [55]Maletzki C Bock S Fruh P Macius K Witt A Prall F. NSG mice as hosts for oncological precision medicine. Lab Invest (2020) 100(1): 27– 37. 10.1038/s41374-019-0298-6 31409886 · DOI
  43. [56]Billerbeck E Horwitz JA Labitt RN Donovan BM Vega K Budell WC. Characterization of human antiviral adaptive immune responses during hepatotropic virus infection in HLA-transgenic human immune system mice. J Immunol (2013) 191(4): 1753–64. 10.4049/jimmunol.1201518 PMC3735836 23833235 · DOI
  44. [57]Kieper WC Jameson SC. Homeostatic expansion and phenotypic conversion of naive T cells in response to self peptide/MHC ligands. Proc Natl Acad Sci USA (1999) 96(23): 13306–11. 10.1073/pnas.96.23.13306 PMC23943 10557316 · DOI
  45. [58]Min B Yamane H Hu-Li J Paul WE. Spontaneous and homeostatic proliferation of CD4 T cells are regulated by different mechanisms. J Immunol (2005) 174(10): 6039–44. 10.4049/jimmunol.174.10.6039 15879097 · DOI

Cited by

Sorted by citations

Authors
Delgobo, M., Heinrichs, M., Hapke, N., Ashour, D., Appel, M., Srivastava, M., Heckel, T., Spyridopoulos, I., Hofmann, U., Frantz, S., & Ramos, G. C.
Affiliations
  • Universitätsklinikum Würzburg (DE)
  • Freeman Hospital (GB)
Corresponding author
Ramos, Gustavo Campos
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2021-02-19
Volume
12
Pages
584538-584538
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2021.584538
PMC
PMC7935504
OpenAlex
W3133110462
Cited by
43
References
13
Citations by year
2026: 7 · 2025: 11 · 2024: 6 · 2023: 11 · 2022: 5 · 2021: 3
FWCI
4.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Online Publication Service of Würzburg University (Würzburg University) (submittedVersion, cc-by)
  • Newcastle University ePrints (Newcastle Univesity) (cc-by)
Funders
  • Deutsche Forschungsgemeinschaft
  • Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Würzburg
  • Bundesministerium für Bildung und Forschung
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
immunosenescence, CD4+ T cells, cardiac aging, terminally differentiated T cells, memory T cells, PD-1, CCR7, CD45RO, myocarditis, monocytes, macrophages, dendritic cells, cardiac transcriptome, xenotransplantation, HLA-DRB1*0101
MeSH terms
RNA-Seq, Aging, Animals, Cell Differentiation, Cells, Cultured, Heart Diseases, Humans, Immunologic Memory, Mice, Inbred C57BL, Mice, Transgenic, Myocardium, Transplantation, Heterologous, CD4-Positive T-Lymphocytes, Gene Expression, Mice, SCID, Mice, Inbred NOD, Mice, Knockout, Mice, HLA-DRB1 Chains

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