CD8+ T Cell Senescence: Lights and Shadows in Viral Infections, Autoimmune Disorders and Cancer

Abstract

CD8⁺ T lymphocytes are a heterogeneous class of cells that play a crucial role in the adaptive immune response against pathogens and cancer. During their lifetime, they acquire cytotoxic functions to ensure the clearance of infected or transformed cells and, in addition, they turn into memory lymphocytes, thus providing a long-term protection. During ageing, the thymic involution causes a reduction of circulating T cells and an enrichment of memory cells, partially explaining the lowering of the response towards novel antigens with implications in vaccine efficacy. Moreover, the persistent stimulation by several antigens throughout life favors the switching of CD8⁺ T cells towards a senescent phenotype contributing to a low-grade inflammation that is a major component of several ageing-related diseases. In genetically predisposed young people, an immunological stress caused by viral infections (e.g., HIV, CMV, SARS-CoV-2), autoimmune disorders or tumor microenvironment (TME) could mimic the ageing status with the consequent acceleration of T cell senescence. This, in turn, exacerbates the inflamed conditions with dramatic effects on the clinical progression of the disease. A better characterization of the phenotype as well as the functions of senescent CD8⁺ T cells can be pivotal to prevent age-related diseases, to improve vaccine strategies and, possibly, immunotherapies in autoimmune diseases and cancer.

Keywords: CD28− CD57+ CD8+ T cells; CMV; HIV; SARS-CoV-2; autoimmune disease; cancer; immune-senescence; infection; inflammaging.

Figure 1

Immunological stress derived from chronic viral infections, autoimmune diseases and tumor conditions fuels the inflammation, typically of low grade during a healthy ageing, favoring the expansion of senescent CD28⁻ CD57⁺ CD8⁺ T cells that, despite the telomere shortening, the higher nuclear p16 and p21 expression, the DNA damage foci could retain proliferative capability and release proteases, interleukins, chemokines and pro-inflammatory factors that feature the specialized secretory activity termed senescence associated secretory phenotype (SASP), thus contributing to the overall inflammation. Senescence-associated β-galactosidase (SA-βGal) activity displays an age-associated increase in CD8⁺ T cell populations.