Restored immune cell functions upon clearance of senescence in the irradiated splenic environment

Aging Cell. 2019 Aug;18(4):e12971. doi: 10.1111/acel.12971. Epub 2019 May 31.


Some studies show eliminating senescent cells rejuvenate aged mice and attenuate deleterious effects of chemotherapy. Nevertheless, it remains unclear whether senescence affects immune cell function. We provide evidence that exposure of mice to ionizing radiation (IR) promotes the senescent-associated secretory phenotype (SASP) and expression of p16INK4a in splenic cell populations. We observe splenic T cells exhibit a reduced proliferative response when cultured with allogenic cells in vitro and following viral infection in vivo. Using p16-3MR mice that allow elimination of p16INK4a -positive cells with exposure to ganciclovir, we show that impaired T-cell proliferation is partially reversed, mechanistically dependent on p16INK4a expression and the SASP. Moreover, we found macrophages isolated from irradiated spleens to have a reduced phagocytosis activity in vitro, a defect also restored by the elimination of p16INK4a expression. Our results provide molecular insight on how senescence-inducing IR promotes loss of immune cell fitness, which suggest senolytic drugs may improve immune cell function in aged and patients undergoing cancer treatment.

Keywords: T cell; ionizing radiation; p16INK4a; senescence; senescent-associated secretory phenotype; spleen.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / therapeutic use
  • Arenaviridae Infections / drug therapy
  • Arenaviridae Infections / immunology
  • Arenaviridae Infections / virology
  • Cell Proliferation / radiation effects
  • Cells, Cultured
  • Cellular Senescence / genetics
  • Cellular Senescence / radiation effects*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Ganciclovir / therapeutic use
  • Lymphocytic choriomeningitis virus / immunology
  • Macrophages / metabolism
  • Mice
  • Mice, Transgenic
  • Phenotype
  • Radiation, Ionizing*
  • Rejuvenation / physiology
  • Spleen / metabolism*
  • Spleen / radiation effects*
  • Spleen / virology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / radiation effects*


  • Antiviral Agents
  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • Ganciclovir