Editorial: The Impact of Immunosenescence and Senescence of Immune Cells on Responses to Infection and Vaccination

Advancing age is characterized by changes in the innate and adaptive immune system termed immunosenescence, which contribute to the pathogenesis of various diseases, increased incidence of infections and reduced response to vaccinations. Antigen sensing, presentation and cytokine responses of innate cells are all altered with age leading to impaired responses to infection and vaccines. Aging affects individual T and B cells throughout their life-cycle, from alterations in hematopoiesis, maturation and homeostasis, to memory generation and effector functions as well as their interactions with other cell types, and the composition and repertoire of the adaptive immune cell compartments. Latent infection with Cytomegalovirus (CMV), has a profound impact on the aging immune system, particularly on the T cell compartment, but also other herpesviruses, e.g., Epstein-Barr virus (EBV) might play a role in T cell aging. Periodical reactivation of these viruses shapes the evolution of the T cell repertoire in aging leading to decreased diversity. The general dogma is that the T cell memory responses generated early in life remain stable as we age. Thus, one of the proposed strategies to improve vaccine responses in the elderly is to vaccinate early before these changes occur. However, Lanfermeijer et al. show that the T cell repertoire for CMV and EBV loses stability with age and becomes less diverse. They also demonstrate that CMV-infection is associated with a decreased diversity of EBV-specific CD8 T cells highlighting the impact of CMV on the T cell response to other pathogens. In the past, life-long repeated antigenic stimulation (e.g., in the context of CMV-infection) was thought to be the only driver of terminal differentiation of T cells. These terminally differentiated T cells, which accumulate with aging, exhibit characteristics of senescence and are frequently thought to be dysfunctional. However, recent data show that senescent-like T cells acquire alternative functions, e.g. Natural Killer (NK) cell characteristics, which are independent of antigen specificity, and that antigen-independent bystander activation of T cells by cytokines may drive senescence as well as expression of NK-like activity in T cells (Abbas and Akbar). Replicative and cellular senescence is frequently studied in cell types such as fibroblasts, but over the last years hallmarks of aging such as DNA damage, the senescenceassociated secretory phenotype (SASP), mitochondrial dysfunction, protein homeostasis etc., have also been investigated in immune cells and have been identified as important players in T cell aging. Using mice with a deficiency in the DNA excision-repair gene Ercc1, Pieren et al. show accumulation of Tregs with an aging-related phenotype and reduced T-cell responsiveness. Edited and reviewed by: Laura Haynes, University of Connecticut, United States