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Expanding Cytotoxic T Lymphocytes from Umbilical Cord Blood that Target Cytomegalovirus, Epstein-Barr Virus, and Adenovirus
Published on: May 7, 2012
Cytotoxic CD4+ T cells eliminate senescent cells by targeting cytomegalovirus antigen
Tatsuya Hasegawa1, Tomonori Oka2, Heehwa G Son2
1Center for Cancer Immunology, Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Shiseido Global Innovation Center, Yokohama, Japan.
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 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.
Insights
A virus-immune axis prevents senescent fibroblast accumulation in aging skin. Cytotoxic CD4+ T cells target and eliminate human cytomegalovirus-infected senescent cells, revealing a novel aging mechanism.
Area of Science:
- Immunology
- Dermatology
- Gerontology
Background:
- Senescent cell accumulation contributes to aging and associated diseases like cancer.
- The mechanisms preventing senescent cell buildup in aging human organs remain largely unknown.
- Understanding these mechanisms is crucial for developing interventions against age-related diseases.
Purpose of the Study:
- To investigate the mechanism controlling senescent fibroblast accumulation in human skin.
- To elucidate the role of the virus-immune axis in regulating cellular senescence.
- To identify potential therapeutic targets for age-related skin conditions.
Main Methods:
- Comparative analysis of senescent fibroblasts in young versus elderly human skin.
- Assessment of immune cell populations, including cytotoxic CD4+ T cells (CD4 CTLs), and cytokine profiles (CXCL9).
- Investigation of antigen presentation by senescent fibroblasts (HLA-II, HCMV-gB) and their interaction with CD4 CTLs.
Main Results:
- Senescent fibroblasts were more prevalent in older skin but did not increase further with advanced age.
- Increased CXCL9 and CD4 CTL recruitment correlated with reduced senescent fibroblast levels.
- Senescent fibroblasts expressing human cytomegalovirus glycoprotein B (HCMV-gB) were identified as targets for HLA-II-dependent elimination by CD4 CTLs.
Conclusions:
- A virus-immune axis, involving human cytomegalovirus (HCMV) reactivation in senescent cells, regulates senescent fibroblast accumulation in human skin.
- Skin-resident CD4 CTLs eliminate senescent cells by recognizing HCMV-gB antigen in an HLA-II-dependent manner.
- This mechanism prevents uncontrolled senescent cell buildup, offering insights into aging and immune surveillance.
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