Senescent cells accumulate with age in large part because the capacity of the immune system to destroy these cells diminishes in late life. Lingering senescent cells disrupt tissue structure and function via their pro-growth, pro-inflammatory secretions. The more senescent cells present in the body, the worse the outcome. Many approaches to the selective destruction of senescent cells are under development, but a greater understanding of the role of the immune system in the natural clearance of senescent cells may open further doors to more effective classes of therapy. The ideal therapy is one that enhances the ability of the immune system to clear undesirable senescent cells, while allowing the short-term existence of senescent cells in response to injury, potentially cancerous tissue, and so forth, scenarios in which senescent cells are beneficial.
In today's open access preprint paper, researchers discuss the role of γδ T cells in the clearance of senescent cells, noting that γδ T cells react to the presence of senescent cells. Interestingly, past research has shown that a subset of γδ T cells become inflammatory in visceral fat tissue, and contribute to the harmful chronic inflammation generated by excess visceral fat. We also know that excess visceral fat produces senescent cells at an accelerated pace, one of the ways in which it can provoke inflammation throughout the body. Joining the dots here, one might speculate that continual generation of senescent cells in sufficient numbers in visceral fat tissue causes the γδ T cell response to become maladaptive, part of the problem rather than part of the solution.
γδ T Cells Target and Ablate Senescent Cells in Aging and Alleviate Pulmonary Fibrosis
A variety of physiological and pathological stimuli elicit the cellular senescence response. Immune cells are known to execute surveillance of infected, cancerous, and senescent cells, and yet senescent cells accumulate with age and drive inflammation and age-related disease. Understanding the roles of different immune cells in senescent cell surveillance could enable the development of immunotherapies against biological aging and age-related disease.
Here, we report the role of human gamma delta (γδ) T cells in eliminating senescent cells. Human donor Vγ9vδ2 T cells selectively remove senescent cells of different cell types and modes of induction while sparing healthy cells, with parallel findings in mouse cells. We find that senescent cells express high levels of multiple γδ T cell ligands, including cell-surface BTN3A1. Individually blocking NKG2D or γδ T cell receptor of γδ T cells only partially reduces Vγ9vδ2 T cell cytotoxicity, evidencing their versatility in senescence removal. γδ T cells expand in response to the induction of a mouse model of idiopathic pulmonary fibrosis (IPF), accompanied by the emergence of senescent cells, and colocalize with senescent cells in lung tissue from patients with IPF. Finally, we show that adoptive cell transfer of γδ T cells into an IPF mouse model reduces the number of p21-expressing senescent cells in affected lung tissue and improves outcomes.
γδ T cells or modalities that activate their surveillance activity present a potent approach for removing senescent cells and their attendant contribution to aging and disease.
View the full article at FightAging
