The ageing immune system and its battle with viruses

The global increase in life expectancy has resulted in a growing proportion of older individuals at increased risk of severe disease outcomes following viral infections. CD8⁺ T cells play a vital role in controlling viral infections and provide protection against severe disease by eliminating virus-infected cells. Furthermore, CD8⁺ T cells recognize conserved internal viral proteins, enabling cross-reactivity and the formation of long-term immunological memory. However, a lifetime of exposures to acute and persistent latent viruses, vaccinations and the age-associated decline in immune functions (immunosenescence and inflammaging) have a profound impact on virus-specific CD8⁺ T cell populations. The age-associated progressive decline of naïve CD8⁺ T cells, reduced T cell receptor (TCR) diversity, the accumulation of highly differentiated memory and/or exhausted CD8⁺ T cells and low-level chronic inflammation directly affect virus-specific immunity. These age-associated changes impair both primary and recall CD8⁺ T cell responses to infections and vaccinations in older individuals. Both ageing and exposure history impact the CD8⁺ T cell correlates of protection, including frequency, phenotype, TCR diversity, polyfunctionality, cytotoxic potential and proliferation capacity. The implications of these changes are discussed in the context of acute (influenza and respiratory syncytial virus), persistent latent (cytomegalovirus, Epstein-Barr virus and varicella-zoster virus) and novel (severe acute respiratory syndrome coronavirus 2) viruses. An in-depth understanding of how lifelong viral exposures intersect with immunosenescence will elucidate how virus-specific CD8⁺ T cells change with age. These insights will aid vaccine strategies to effectively harness CD8⁺ T cells and induce long-lasting, broadly reactive virus-specific immunity.