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

Tatsuya Hasegawa¹, Tomonori Oka², Heehwa G Son², Valeria S Oliver-García², Marjan Azin², Thomas M Eisenhaure³, David J Lieb³, Nir Hacohen⁴, Shadmehr Demehri⁵

Affiliations

¹ Center 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. Electronic address: tatsuya.hasegawa@shiseido.com.
² Center 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.
³ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Center for Cancer Immunology, Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Center 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. Electronic address: sdemehri1@mgh.harvard.edu.

PMID: 37001502
DOI: 10.1016/j.cell.2023.02.033

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

Tatsuya Hasegawa et al. Cell. 2023.

. 2023 Mar 30;186(7):1417-1431.e20.

doi: 10.1016/j.cell.2023.02.033.

Authors

Tatsuya Hasegawa¹, Tomonori Oka², Heehwa G Son², Valeria S Oliver-García², Marjan Azin², Thomas M Eisenhaure³, David J Lieb³, Nir Hacohen⁴, Shadmehr Demehri⁵

Affiliations

¹ Center 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. Electronic address: tatsuya.hasegawa@shiseido.com.
² Center 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.
³ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Center for Cancer Immunology, Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Center 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. Electronic address: sdemehri1@mgh.harvard.edu.

PMID: 37001502
DOI: 10.1016/j.cell.2023.02.033

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.

Keywords: aging; antiviral immunity; cytomegalovirus; cytotoxic CD4(+) T cell; fibroblast; glycoprotein B; senescent cell; skin.

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Conflict of interest statement

Declaration of interests T.H. and S.D. are co-inventors on a filed patent application for the use of a cytomegalovirus vaccine to treat aging-associated diseases.

Comment in

"Age could not wither her…" because of her cytotoxic CD4⁺ T cells?
Guy T, Pillai S. Guy T, et al. Sci Immunol. 2023 May 12;8(83):eadi4345. doi: 10.1126/sciimmunol.adi4345. Epub 2023 May 5. Sci Immunol. 2023. PMID: 37146129
Boosting T cell immunity against cytomegalovirus: a potential strategy combating human aging and age-related diseases.
Wirth M, Brenner W, Krämer OH. Wirth M, et al. Signal Transduct Target Ther. 2023 Sep 1;8(1):325. doi: 10.1038/s41392-023-01590-6. Signal Transduct Target Ther. 2023. PMID: 37652938 Free PMC article. No abstract available.

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

Affiliations

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

Authors

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Abstract

Conflict of interest statement

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