Senescence‐induced changes in CD4 T cell differentiation can be alleviated by treatment with senolytics

Abstract

Aging and senescence impact CD4 T helper cell (Th) subset differentiation during influenza infection. In the lungs of infected aged mice, there were significantly greater percentages of Th cells expressing the transcription factor FoxP3, indicative of regulatory CD4 T cells (Treg), when compared to young. TGF‐beta levels, which drive FoxP3 expression, were also higher in the bronchoalveolar lavage of aged mice and blocking TGF‐beta reduced the percentage of FoxP3+ Th in aged lungs during influenza infection. Since TGF‐beta can be the product of senescent cells, these were targeted by treatment with senolytic drugs. Treatment of aged mice with senolytics prior to influenza infection restored the differentiation of Th cells in those aged mice to a more youthful phenotype with fewer Th cells expressing FoxP3. In addition, treatment with senolytic drugs induced differentiation of aged Th toward a healing Type 2 phenotype, which promotes a return to homeostasis. These results suggest that senescent cells, via production of cytokines such as TGF‐beta, have a significant impact on Th differentiation.

A diminished immune response underlies age-related SARS-CoV-2 pathologies

“…Enhanced populations of these cells could possibly lead to induction of IL-17-producing cells and then to the recruitment of neutrophils to the lung-a hallmark of COVID-19 (Blanco-Melo et al, 2020). These data are in agreement with recent findings implicating elevated levels of TGF-b from senescent cells, which we also find to be increased in number in aged animals (Lorenzo et al, 2022). This biology would explain why we see a significant increase of neutrophils in the respiratory tract of older individuals, as TGF-b signaling induces IL-17, which in turn mediates neutrophil recruitment.…”

Cellular senescence is a key mediator of lung aging and susceptibility to infection

“…Recently, studies from our lab and others have begun to apply senolytic strategies to overcome age-related deficits during an infection. Our work with flu infection demonstrated that treatment of aged mice with D+Q decreased the proportion of Tregs in the lungs during infection in favor of a more healing GATA-3 expressing Th2 T cell population by mitigating the senescent environment ( 145 ). Strikingly, D+Q treatment completely abrogated TGF-β production in the lung following infection.…”

How Can We Improve the Vaccination Response in Older People? Part II: Targeting Immunosenescence of Adaptive Immunity Cells

“…On the other hand, the so-called “anti-aging drugs”, senolytics, promote removal of senescent immune cells that accumulate with age [ 170 ]. Specifically, in old mice, it has been demonstrated that senolytic drugs can impact CD4 + T cells, most likely by modulating the microenvironment, which can then positively influence T cell differentiation during the response to influenza infection [ 171 ].…”