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

Abstract

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 compared with young skin. However, they did not increase with advancing age in the elderly. Increased CXCL9 and cytotoxic CD4+ T cell (CD4 CTL) 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 CTL eliminated HCMV- gB+ senescent fibroblasts in an HLA-II-dependent manner, and HCMV-gB activated CD4 CTL from the human skin. Collectively, our findings demonstrate HCMV reactivation in senescent cells, which can be directly eliminated by CD4 CTL through the recognition of the HCMV-gB antigen.

NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates

“…Although NKG2D-CAR T cells have shown a favorable safety profile in cancer clinical trials, it is essential to thoroughly investigate their safety and potential toxicities in older individuals through clinical studies. NKG2DLs are highly expressed in senescent cells from aged individuals ( 50 ), and our studies demonstrated that NKG2D-CAR T cells do not exhibit overt toxicity in aged mice and nonhuman primates. These findings suggest that the adoptive transfer of engineered T cells armed with NKG2D-CAR, specifically targeting naturally occurring senescent cells expressing NKG2DLs, could have an impact on the field of geriatric medicine.…”

“…Although it was previously reported that senescent cells escape from endogenous NKG2D-mediated NK cell immunosurveillance during aging ( 18 ), our results demonstrate that senescent cells expressing NKG2DLs in vivo can be selectively and effectively eliminated by the adoptive transfer T cells armed with NKG2D-CARs. Recent studies have found higher expression of NKG2DLs (ULBP2 and MICA) in senescent fibroblasts present in the skin of older individuals in comparison with younger individuals ( 50 ). Our studies indicate that senescent cells expressing NKG2DLs in aged humans could potentially be targeted using NKG2D-CAR T cells.…”

Energy metabolism as therapeutic target for aged wound repair by engineered extracellular vesicle

“…Dermal fibroblasts were isolated from collected skin samples in wound healing assay, according to previous reports ( 9 , 75 ). After removing subcutaneous fat tissues with a scalpel, skin tissues were incubated in Elastase (0.12 mg/ml; STEMCELL, #07453) in DMEM at 37°C for 25 min to separate dermal and epidermal.…”

“…Senescent cells (SnCs) accumulate in tissues with aging, contributing to the development of age-related pathologies and declines, mainly via senescence-associated secretory phenotype (SASP) ( 6 – 8 ). Through secreting proinflammatory and tissue-remodeling factors, SnCs communicate with surroundings and fuel a chronic inflammatory microenvironment in the body, which seriously impedes the damaged tissue repair ( 9 , 10 ). Moreover, SnCs are characterized with DNA damage, cell cycle arrest, metabolic changes, mitochondria dysfunctions, and reduced autophagy, underlying the impaired capacity for wound repair in aging tissues ( 8 , 11 , 12 ).…”

Escape from senescence: molecular basis and therapeutic ramifications

“…The escape‐from‐senescence phenomenon could also be a mechanism contributing to this outcome (see the next section). Ever since GL13 discovery, the spectrum of pathological entities has been expanded to include benign, preneoplastic, and neoplastic lesions, while senescent cells have also been recognised in various experimental and ageing contexts (Table 2) [37,106,107,110–137]. In particular, in clinical settings, skin pathologies (nevi, seborrheic, and actinic keratoses), lung, pancreatic, urothelial and laryngeal precancerous lesions, various types of carcinomas following treatment, sarcomas, haematological malignancies (Langerhans histiocytosis), and a variety of tissues from aged organs were included (Table 2).…”