Centromere structure as a novel pathway regulating immune cell aneuploidy associated with aging

Helena Izquierdo Fernández (Institut Curie, Paris)

27 June 2024


Pratical info

12:00 - 13:00
Conference room Rosalind Franklin
Reduced mobility access

Aging is associated with the accumulation of senescent cells and the increase of systemic inflammation. At the cellular level, aneuploidy gradually increases with age, suggesting that centromeric function may be dysregulated during aging, thereby contributing to senescence and inflammaging. Here, we investigated the regulation of centromere integrity in T lymphocytes, which exhibit age-associated aneuploidy and senescent cell accumulation. We have found that resting human lymphocytes from adults harbor a significant population of cells expressing low levels of total CENP-A, while CENP-B and CENP-C levels are not affected. Notably, CENP-A-low cells show lower or non-detectable CENP-A loaded at centromeres, indicating a change in centromere identity. In contrast, T cells from newborns do not exhibit this population.

Furthermore, CENP-A-low T cells are not equally distributed among subsets of adult T cells. This indicates that the CENP-A-low state is associated with age-dependent changes and the functional state of T cells. In vitro, activated T cells in which we have recapitulated this defective centromere structure by genetic knock-out of CENP-A, show a senescent phenotype characterized by the upregulation of p53 target genes and the expression of proinflammatory genes. In addition, CENP-A knock-out T cells display chromosome-specific aneuploidy after proliferation. Overall, our results reveal that centromere structure integrity is impacted through lifespan and determines aneuploidy in T cells, contributing to regulation of senescence and inflammation.

Invited by Suzanne Faure-Dupuy, Alberto De la Iglesia and Hugo Barreto, as part of the Post-doc seminar series.

Selected publications

  • Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria. Rosain J, Neehus AL, Manry J, Yang R, Le Pen J, Daher W, Liu Z, Chan YH, Tahuil N, Türel Ö, Bourgey M, Ogishi M, Doisne JM, Izquierdo HM, et al. Cell. 2023 Feb 2;186(3):621-645.e33. doi: 10.1016/j.cell.2022.12.038. PMID: 36736301
  • A genetic memory initiates the epigenetic loop necessary to preserve centromere position. Hoffmann S, Izquierdo HM, Gamba R, Chardon F, Dumont M, Keizer V, Hervé S, McNulty SM, Sullivan BA, Manel N, Fachinetti D. EMBO J. 2020 Oct 15;39(20):e105505. doi: 10.15252/embj.2020105505. Epub 2020 Sep 18. PMID: 32945564
  • Von Hippel-Lindau Protein Is Required for Optimal Alveolar Macrophage Terminal Differentiation, Self-Renewal, and Function. Izquierdo HM, Brandi P, Gómez MJ, Conde-Garrosa R, Priego E, Enamorado M, Martínez-Cano S, Sánchez I, Conejero L, Jimenez-Carretero D, Martín-Puig S, Guilliams M, Sancho D. Cell Rep. 2018 Aug 14;24(7):1738-1746. doi: 10.1016/j.celrep.2018.07.034. PMID: 30110631
  • Lung CD103+ dendritic cells restrain allergic airway inflammation through IL-12 production. Conejero L, Khouili SC, Martínez-Cano S, Izquierdo HM, Brandi P, Sancho D. JCI Insight. 2017 May 18;2(10):e90420. doi: 10.1172/jci.insight.90420. eCollection 2017 May 18. PMID: 28515363
  • Leishmania Uses Mincle to Target an Inhibitory ITAM Signaling Pathway in Dendritic Cells that Dampens Adaptive Immunity to Infection. Iborra S, Martínez-López M, Cueto FJ, Conde-Garrosa R, Del Fresno C, Izquierdo HM, Abram CL, Mori D, Campos-Martín Y, Reguera RM, Kemp B, Yamasaki S, Robinson MJ, Soto M, Lowell CA, Sancho D. Immunity. 2016 Oct 18;45(4):788-801. doi: 10.1016/j.immuni.2016.09.012. Epub 2016 Oct 11. PMID: 27742545