Human T Cell Aging and the Impact of Persistent Viral Infections

Abstract

Aging is associated with a dysregulation of the immune response, loosely termed “immunosenescence.” Each part of the immune system is influenced to some extent by the aging process. However, adaptive immunity seems more extensively affected and among all participating cells it is the T cells that are most altered. There is a large body of experimental work devoted to the investigation of age-associated differences in T cell phenotypes and functions in young and old individuals, but few longitudinal studies in humans actually delineating changes at the level of the individual. In most studies, the number and proportion of late-differentiated T cells, especially CD8+ T cells, is reported to be higher in the elderly than in the young. Limited longitudinal studies suggest that accumulation of these cells is a dynamic process and does indeed represent an age-associated change. Accumulations of such late-stage cells may contribute to the enhanced systemic pro-inflammatory milieu commonly seen in older people. We do not know exactly what causes these observed changes, but an understanding of the possible causes is now beginning to emerge. A favored hypothesis is that these events are at least partly due to the effects of the maintenance of essential immune surveillance against persistent viral infections, notably Cytomegalovirus (CMV), which may exhaust the immune system over time. It is still a matter of debate as to whether these changes are compensatory and beneficial or pathological and detrimental to the proper functioning of the immune system and whether they impact longevity. Here, we will review present knowledge of T cell changes with aging and their relation to chronic viral and possibly other persistent infections.

Immunomodulatory role of high-density lipoproteins: impact on immunosenescence

“…These investigations may eventually lead to the development of lipidbased immunotherapies or adjuvants that can be used to boost host protection in the elderly. In particular, it is important to point out that the present study cannot determine if the effect observed is specific for a particular subset of T cells (Fülöp et al 2013) even if our recent published data suggest that the CD45RA or CD45RO T cell subpopulations cannot explain changes in the signal transduction of T cells with aging . Nevertheless, the data provide support for an important role for HDL in the altered response of T cells in aging, revealing additional clues to unravel the underlying mechanisms of immunosenescence which are under current investigations in our laboratories especially addressing this question in T cell subpopulations.…”

“…Although the underlying causes that link human aging to increased risk of pathology is not fully understood, it is clear that alterations in immune functions play a critical role (Pawelec 2012;Fulop et al 2005;López-Otín et al 2013). Numerous studies of age-related immune dysfunction, or "immunosenescence," have been published (Fülöp et al 2013;Larbi et al 2013), but the conclusions drawn from these investigations remain controversial. The direct clinical consequences of age-related immune dysfunction seem clear and are well demonstrated by the increased rate and severity of infections, cancers, and autoimmune disorders observed in the elderly.…”

“…Immunosenescence should perhaps be considered to represent the dysregulation of a system that is constantly trying to adapt and maintain homeostasis in the face of diverse inputs and outputs that are still only crudely defined (Pawelec 2012). Studies of elderly humans and animal models have revealed that production of interleukin-2 (IL-2) and clonal expansion of effector and memory T cells are the aspects of the immune system which are the most susceptible to agerelated alterations (Fülöp et al 2013). It is therefore possible that changes in cell membrane biology and disruption of the proximal signaling events may contribute to these altered functions (Larbi et al 2011;Goronzy et al 2012;Fulop et al 2014).…”

Early-onset Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency

“…8 Premature immunosenescence can occur as a consequence of chronic immune stimulation, such as persistent viral infections. 9 In addition, genetic factors favoring premature differentiation and/or persistence of senescent immune cells could be a predisposing factor for autoimmunity, even in the absence of persistent infections.…”

Individual Risk Detection of Developing Cognitive Decline and Dementia in Adults with Down’s Syndrome

“…Some investigation reported that HHV-6 positivity was higher in AD than age-matched control brains [22,26]. However, another investigation [27] was not able to confirm these findings.…”