T Cell Immunosenescence after Early Life Adversity: Association with Cytomegalovirus Infection

Abstract

Early life adversity (ELA) increases the risk for multiple age-related diseases, such as diabetes type 2 and cardiovascular disease. As prevalence is high, ELA poses a major and global public health problem. Immunosenescence, or aging of the immune system, has been proposed to underlie the association between ELA and long-term health consequences. However, it is unclear what drives ELA-associated immunosenescence and which cells are primarily affected. We investigated different biomarkers of immunosenescence in a healthy subset of the EpiPath cohort. Participants were either parent-reared (Ctrl, n = 59) or had experienced separation from their parents in early childhood and were subsequently adopted (ELA, n = 18). No difference was observed in telomere length or in methylation levels of age-related CpGs in whole blood, containing a heterogeneous mixture of immune cells. However, when specifically investigating T cells, we found a higher expression of senescence markers (CD57) in ELA. In addition, senescent T cells (CD57+) in ELA had an increased cytolytic potential compared to senescent cells in controls. With a mediation analysis we demonstrated that cytomegalovirus (CMV) infection, which is an important driving force of immunosenescence, largely accounted for elevated CD57 expression observed in ELA. Leukocyte telomere length may obscure cell-specific immunosenescence; here, we demonstrated that the use of cell surface markers of senescence can be more informative. Our data suggest that ELA may increase the risk of CMV infection in early childhood, thereby mediating the effect of ELA on T cell-specific immunosenescence. Thus, future studies should include CMV as a confounder or selectively investigate CMV seronegative cohorts.

From early adversities to immune activation in psychiatric disorders: the role of the sympathetic nervous system

“…Collectively, these results suggest that ELA exposure is associated with a sustained activation of adaptive immunity and accelerated immune ageing, as indexed by the increase in T cell senescence. These effects appeared to be independent of either stress or health‐risk behaviours, suggestive of a primary effect of early life programming on specific immune cell populations . Exploring how social adversity may affect peripheral immune cells, Counotte et al .…”

“…These changes were further accompanied by decreased percentages of natural killer (NK; CD3 -/CD56 + ) and NK T cells (CD3 + /CD56 + ) [19]. Comparing individuals separated from their mothers in early life to those reared by their parents, Elwenspoek and colleagues also reported increased T cell senescence (CD57 + cells) [20]. In another FACS study from this group, comparing individuals with a history of ELA to those without, a reduction in the numbers of CD69 + /CD8 + T cells and increased numbers of human leucocyte antigen D-related HLA-DR + /CD4 + , HLA-DR + / CD8 + and CD25 + /CD8 + T cells was reported [21].…”

“…Collectively, these results suggest that ELA exposure is associated with a sustained activation of adaptive immunity and accelerated immune ageing, as indexed by the increase in T cell senescence. These effects appeared to be independent of either stress or health-risk behaviours, suggestive of a primary effect of early life programming on specific immune cell populations [20][21][22]. Exploring how social adversity may affect peripheral immune cells, Counotte et al observed that individuals with high clinical risk for psychosis who were exposed to ELA were characterized by an increased number of CD4 + T helper type 17 (Th17) cells when compared with those at lower risk [23].…”

From feedback loop transitions to biomarkers in the psycho-immune-neuroendocrine network: Detecting the critical transition from health to major depression

“…Abnormal GR activity and glucocorticoid resistance may precipitate dysfunction in T cell maturation and function, worsening immune defense and risk of infection. Despite limited analyses in MDD, susceptibility to streptococcal infection is increased in children exposed to acute or chronic family stress (Meyer & Haggerty, 1962), low socioeconomic status increases respiratory infection in association with T cell telomere shortening (Cohen et al, 2013), and similar T cell senescence with early life adversity is linked to increased cytomegalovirus infection (Elwenspoek et al, 2017). T cells not only perform a surveillance function (Baruch & Schwartz, 2013), but regulate neurogenesis and neuroplasticity (Ziv & Schwartz, 2008), and protect against maladaptive behavioural responses (Lewitus et al, 2009).…”

Environmental Impact on Health across Generations: Policy Meets Biology. A Review of Animal and Human Models

“…This mode of protection is typically lost when maternally derived antibodies are degraded, but the maturing offspring immune system's ability to generate its own effective adaptive immunity replaces it [56]. A wide body of research highlights the fundamental role early-life environment plays in determining the broad transcriptional identity of circulating lymphocytes and showing that the early-life environment has a very strong influence on T-cells [57][58][59][60][61][62].…”