Researchers here investigate one of the mechanisms by which the immune system recognizes senescent cells, targeting them for destruction. Accumulating numbers of senescent cells are one of the contributing causes of aging, and the age-related decline of the immune system probably accelerates this process in later life. In theory, given a good enough understanding of the biochemistry involved, it should be possible to greatly increase the efficiency with which the immune system destroys senescent cells. This is not the direction taken by the first companies to work on senescent cell clearance technologies, however, so this approach may never be developed, as it will prove to be unnecessary.
Senescent cells are specifically recognized and eliminated by natural killer (NK) cells. In this study we investigated the mechanisms which control the recognition of senescent cells by NK cells. We found that senescent cells up-regulate the expression of NKG2D ligands MICA and ULBP2 regardless of the senescence-inducing stimuli. The mechanisms regulating the expression of NKG2D ligands in senescent cells are partly attributed to a DNA damage response and activation of ERK activity. MICA and ULBP2 were found to be localized at the cell membrane where they can interact with NK cells to mediate efficient killing of senescent cells. Interaction of the ligands with the NKG2D receptor on the NK cells is necessary for the recognition of senescent cells by the NK cells in vitro. Importantly, NKG2D receptor-ligand interaction is essential for efficient elimination of senescent cells in vivo and thus for restraining fibrosis development. Overall, our findings demonstrate that NKG2D ligands on senescent cells are necessary for efficient recognition and elimination of senescent cells in vitro and during tissue damage in vivo.
The increase in expression of NKG2D ligands, particularly MICA and ULBP2, is likely a general feature of human senescent cells. A number of other studies have demonstrated the expression of MICA and/or ULBP2 in senescent cells derived from different cell types. Furthermore, senescent cells also acquire unique NKG2D ligand expression profiles consisting of several additional NKG2D ligands that result from differences between cell types (or cell-strains) and the mechanism by which senescence was induced. The repertoire of NKG2D ligands in mice is vast and similar to human cells, however based on sequence comparisons, mouse ligands are not homologous to the human ligands. Of note, NKG2D ligands are present on mouse cells that become senescent following p53 reactivation, and participate in the interaction of these cells with NK cells. In addition to their expression in senescent cells, NKG2D ligands are upregulated in other cell contexts related to cellular stress, including cancer, virally infected cells or following DNA damage. Therefore, the expression of these ligands might be part of a general stress response of cells that is utilized by senescent cells.
Our findings add to the emerging conceptual idea that the senescent program might represent a change in cell state that is associated with conversion to an immunogenic phenotype, functioning to remove damaged cells by immune clearance rather than through apoptosis. In addition to the upregulation of NKG2D ligands, the secretion of chemoattractants or the expression of adhesion molecules are further examples by which senescent cells become immunogenic. Immune clearance of senescent cells is likely beneficial in complex organisms where the regenerative capacity is dependent on non-resident stem cell populations and therefore temporal preservation of tissue architecture is necessary. Elimination of senescent cells following short-term insults, mediated by immune clearance, has physiological functions in tumor suppression and wound healing. Moreover, inefficient clearance might lead to the long-term persistence of senescent cells in tissues that has been associated with promotion of cancer development, ageing and age-related disease. Therefore, understanding the normal processes and mechanisms by which senescent cells are eliminated by the immune system will enable the formulation of conjectures concerning the mechanism responsible for impaired senescent cells elimination in later life. Such an understanding could lead to novel therapeutic strategies that enhance elimination of senescent cells by the immune system to improve tissue repair, cancer therapy and prevent deleterious effects of accumulation of senescent cells.