The loss of naïve T cells is a hallmark of immune aging. Although thymic involution is a primary driver of this naïve T cell loss, less is known about the contribution of other mechanisms to the depletion of naïve T cells in aging primates. We examined the role of homeostatic cycling and proliferative expansion in different T cell subsets of aging rhesus macaques (RM). BrdU incorporation and the expression of the G1-M marker Ki-67 were elevated in peripheral naïve CD4 and even more markedly in the naïve CD8 T cells of old, but not young adult, RM. Proliferating naïve cells did not accumulate in old animals. Rather, the relative size of the naïve CD8 T cell compartment correlated inversely to its proliferation rate. Likewise, T cell receptor diversity decreased in individuals with elevated naïve CD8 T cell proliferation. This apparent contradiction was explained by a significant increase in turnover concomitant with the naïve pool loss. The turnover increased exponentially when the naïve CD8 T cell pool decreased below 4% of total blood CD8 cells. These results link the shrinking naïve T cell pool with a dramatic increase in homeostatic turnover, which has the potential to exacerbate the progressive exhaustion of the naïve pool and constrict the T cell repertoire. Thus, homeostatic T cell proliferation exhibits temporal antagonistic pleiotropy, being beneficial to T cell maintenance in adulthood but detrimental to the long-term T cell maintenance in aging individuals.aging ͉ CD8 ͉ homeostasis T he immune system undergoes dramatic age-related changes in both structure and function. Of these, the best investigated and the most pronounced are the changes affecting aging T cells. Age-related changes were seen in T cell subset representation and T cell diversity in humans (1-3) and experimental animals (4, 5) and have been associated with higher mortality in the aging humans (6, 7). Moreover, impaired T cell activation has been documented in senescent rodent and human T cells (8)(9)(10)(11). Although the molecular lesions in T cell activation have been thoroughly studied, the picture of the age-related dysregulation of T cell populations is still emerging.Optimal protection against new or evolving pathogens requires a reserve of naïve T cells. However, naïve T cell production is reduced in old age because of the involution of the thymus. The maintenance of the naïve T cell compartment is further challenged by the lifelong consumption of naïve cells that respond to acute and persistent infections and become memory T cells. With age, the balance between naïve and antigenselected memory cells changes in favor of the latter, reducing the diversity of T cell receptors (TCRs). In fact, the aging naïve T cell population is reduced in both relative and absolute terms, suggesting that homeostatic mechanisms that maintain the size and the clonal diversity of the T cell repertoire progressively break down (12)(13)(14).T cells can also be replenished by extrathymic mechanisms, which rely on homeostatic proliferation in the absenc...
Aging is usually accompanied by diminished immune protection upon infection or vaccination. While aging results in well-characterized changes in the T-cell compartment of long-lived, outbred, and pathogen-exposed organisms, their relevance for primary antigen responses remain unclear. Therefore, it remains unclear whether and to what extent the loss of naïve T-cells, their partial replacement by oligoclonal memory populations, and the consequent constriction of T-cell receptor (TCR) repertoire, limit the antigen responses in aging primates.
Background Phthalates are associated with increased blood pressure in children. Large exposures to di-(2-ethylhexyl) phthalate (DEHP) among premature infants have been a cause for concern. Methods We conducted a prospective observational cohort study to determine if DEHP exposures are related to systolic blood pressure (SBP) in premature infants, and if this exposure is associated with activation of the mineralocorticoid receptor (MR). Infants were monitored longitudinally for 8 months from birth. Those who developed idiopathic hypertension were compared with normotensive infants for DEHP exposures. Appearance of urinary metabolites after exposure was documented. Linear regression evaluated the relationship between DEHP exposures and SBP index and whether urinary cortisol/cortisone ratio (a surrogate marker for 11β-HSD2 activity) mediated those relationships. Urinary exosomes were quantified for sodium transporter/channel expression and interrogated against SBP index. Results Eighteen patients met the study criteria, nine developed transient idiopathic hypertension at a postmenstrual age of 40.6 ± 3.4 weeks. The presence of urinary DEHP metabolites was associated with prior IV and respiratory tubing DEHP exposures ( p < 0.05). Both IV and respiratory DEHP exposures were greater in hypertensive infants ( p < 0.05). SBP index was related to DEHP exposure from IV fluid ( p = 0.018), but not respiratory DEHP. Urinary cortisol/cortisone ratio was related to IV DEHP and SBP index ( p < 0.05). Sodium transporter/channel expression was also related to SBP index ( p < 0.05). Conclusions Increased blood pressure and hypertension in premature infants are associated with postnatal DEHP exposure. The mechanism of action appears to be activation of the MR through inhibition of 11β-HSD2. Electronic supplementary material The online version of this article (10.1007/s00467-019-04244-4) contains supplementary material, which is available to authorized users.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.