Human Cytomegalovirus as a driving force towards Immunosenescence

Abstract

As the number of elderly in the human population is increasing, aging is becoming a severe problem, especially for public health. The importance of understanding this development is highlighted by the vulnerability of the elderly for injuries and their increased need for medical care. With regard to pathogen defense, aging is associated with a significant decrease in immune system functions. This phenomenon, known as ‘immunosenescence’, is correlated with alteration in T cell populations, namely the expansion of highly differentiated memory T cells and the decrease of naive cells. However, immunosenescence may not be driven solely by chronological aging. Also, chronic antigenic exposure caused, for instance, by latent viral infections may contribute to the deteriorations. Our study aims to dissect the effect of persistent infection on the aging of the immune system. We specifically focussed on the trajectory of memory T cell differentiation caused by chronic CMV infection. For this, we analyzed the cytokine profiles and T cell phenotypes of blood samples from two cohorts of 267 young (age: 21 yrs) and 250 elderly Singaporeans (age: 74 yrs). While aging is known to be associated with an increased level of pro-inflammatory molecules (low-grade inflammation), we could not detect such an increase in the young CMV+ individuals. Notably, however, in this group, we observed CMV-associated alterations T cell populations that closely resembled the senescence-related profile of the elderly. This was evident for instance in a significant increase in the TEM and TTE populations of both CD4+ and CD8+ T cells, a key marker for defining immunosenecence. This senescence-specific shift was apparently specific for CMV infection, as other latent infections in the young by Helicobacter pylori and herpes simplex virus-2 did not induce detectable alterations in T cell populations. Our work thus demonstrates that primary CMV infection has a strong impact on the shaping of the T cell senescence profile. Preliminary data from a NSG humanized mouse model we established may further help to evaluate the effects of persistent CMV infection on T cells early in life and their contribution to the immunological trajectories of aging.