Senescent Cells Negatively Affect T Helper Cell Differentiation

The accumulation of senescent cells with age harms tissues and cell behavior throughout the body. Senescent cells generate a pro-growth, pro-inflammation mix of molecules, the senescence-associated secretory phenotype (SASP). Researchers are still comparatively early in the process of producing a complete list of problems caused by the SASP. One of the better studied SASP components is TGF-β, and here researchers demonstrates that it causes disarray in the normal behavior of T-helper cells of the adaptive immune system. Applying senolytic treatments that selectively destroy senescent cells can reverse this aspect of aging, along with many others that are caused in part by senescent cells.

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.


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