Cytotoxic CD4+ T cells eliminate senescent cells by targeting cytomegalovirus antigen

Senescent cell accumulation has been implicated in the pathogenesis of aging-associated diseases, including cancer. The mechanism that prevents the accumulation of senescent cells in aging human organs is unclear. Here, we demonstrate that a virus-immune axis controls the senescent fibroblast accumulation in the human skin. Senescent fibroblasts increased in old skin compared with young skin. However, they did not increase with advancing age in the elderly. Increased CXCL9 and cytotoxic CD4+ T cells (CD4 CTLs) recruitment were significantly associated with reduced senescent fibroblasts in the old skin. Senescent fibroblasts expressed human leukocyte antigen class II (HLA-II) and human cytomegalovirus glycoprotein B (HCMV-gB), becoming direct CD4 CTL targets. Skin-resident CD4 CTLs eliminated HCMV-gB+ senescent fibroblasts in an HLA-II-dependent manner, and HCMV-gB activated CD4 CTLs from the human skin. Collectively, our findings demonstrate HCMV reactivation in senescent cells, which CD4 CTLs can directly eliminate through the recognition of the HCMV-gB antigen. [Display omitted] •Senescent fibroblasts do not increase with advancing age in the skin of the elderly•CD4 CTLs negatively correlate with senescent fibroblast accumulation in the old skin•Senescent fibroblasts highly express HLA-II, NKG2D ligands, and HCMV-glycoprotein B•CD4 CTLs eliminate HCMV-gB+ senescent fibroblasts in an HLA-II-dependent manner In humans, senescent fibroblasts do not seem to increase with advancing age in the elderly because their populations are controlled by cytotoxic CD4+ T cells. The expression of T cell-activating ligands and the human cytomegalovirus glycoprotein B marks the senescent fibroblasts for elimination.