Mechanisms Underlying T Cell Immunosenescence: Aging and Cytomegalovirus Infection

Abstract

The ability of the human immune system to protect against infectious disease declines with age and efficacy of vaccination reduces significantly in the elderly. Aging of the immune system, also termed as immunosenescence, involves many changes in human T cell immunity that is characterized by a loss in naïve T cell population and an increase in highly differentiated CD28- memory T cell subset. There is extensive data showing that latent persistent human cytomegalovirus (HCMV) infection is also associated with age-related immune dysfunction in the T cells, which might enhance immunosenescence. Understanding the molecular mechanisms underlying age-related and HCMV-related immunosenescence is critical for the development of effective age-targeted vaccines and immunotherapies. In this review, we will address the role of both aging and HCMV infection that contribute to the T cell senescence and discuss the potential molecular mechanisms in aged T cells.

Keywords: HCMV infection; aging; epigenetic regulation; immunosenescence; naive and memory T cells; vaccination.

Figure 1

Model of age- and HCMV-related immunosenescence. Thymic involution contributes to reduced naïve T cell export and T cell diversity with age. To compensate for inadequate thymic export, existing naïve T cells increase homeostatic turnover. Upon antigen stimulation, a large number of terminally differentiated CD45RA⁺CD8⁺ TEM cells clonally expand in the elderly, which dominate the memory pool and further restrict repertoire diversity. These senescent CD45RA⁺ memory T cells typically have diminished T cell responses to stimulation in the absence of CD28 co-stimulatory signaling pathways and are characterized by a variety of altered transcriptional profiles which are epigenetically regulated (including by DNA methylation, histone modifications, microRNAs, and chromatin remodeling). In addition, HCMV infection can result in CD4⁺ naïve pool depletion and memory inflation, which further accelerate immunosenescence in aged individuals. Together, age and HCMV infection contribute to the overall decline in immune function decline and impair the T cell response to vaccines in the elderly.