CD4 T Cells Acquire Cytotoxic Properties to Modulate Cellular Senescence and Aging

Aging is characterized by the progressive deterioration of tissue structure and function, leading to increased vulnerability to diseases and, eventually, death. One prominent process in aging is the accumulation of senescent cells. Although the immune system has been recognized as crucial for the elimination of senescent cells, the associated mechanisms remain incompletely understood. Here we show that CD4 T cells differentiate into cytotoxic T lymphocytes (CTLs) in a senescent cell-rich environment and that a reduction in the senescent cell load, achieved using chemical senolytic drugs, was sufficient to halt this differentiation. We further demonstrate that eliminating CD4 CTLs in the context of late aging by selectively deleting the Eomes transcription factor in CD4 T cells resulted in the increased accumulation of senescent cells, profound physical deterioration, and a decreased life span. In liver cirrhosis, a model of localized chronic inflammation, CD4 CTL elimination increased the senescent load and worsened the disease. Collectively, our findings demonstrate the fundamental role of CD4 CTLs in modulating tissue senescence and unveil a new aspect of age-related T-cell biology implicated in disease susceptibility and longevity. ### Competing Interest Statement Patent application- Monsonego, A., & Elyahu, Y. (2023). "Immune system restoration by cell therapy." U.S. Patent Application No. 18/043,576 (pending), EU patent application No. 21863834.4 (pending), Israel patent application No. 301045 (pending). A related specific aspect of the manuscript covered in this patent application is the emphasis on CD4 CTLs as a potential biomarker of cellular senescence and treatment of aging and age-related diseases involving senescent cell accumulation and immune system restoration.