Cell recovery was assessed after 48 h by flow-based cell counting after PI staining. nave CD4 T cells from older individuals failed to downregulate cytoplasmic zinc, resulting in excessive induction of metallothioneins. Activation-induced metallothioneins regulated the redox state in activated T cells and accounted for an increased proliferation of aged CD4 T cells, suggesting that regulation of T cell zinc homeostasis functions as a compensatory mechanism to preserve the replicative potential of nave CD4 T cells with age. 3-Methylcrotonyl Glycine == Introduction == With increasing age, the abilityof the immune system to protect against new antigenic challenges or to control chronic infections erodes. The epidemiology of infectious diseases such as influenza infections1,2or reactivation of herpes zoster3has been useful in defining the timeframe of this age-dependent decline in immunocompetence. Already between the ages of 50 and 70 years, incidence rates and morbidity of infectious diseases start to increase. in the subsequent decades of life, immune failure accelerates and is a major contribution to morbidity and mortality in the elderly.4,5 The focus of immunosenescence research has been predominantly around the adaptive immune system, given that antiviral and vaccine responses are affected.68To initiate an immune response, T cells need to interact with functional antigen-presenting cells to become activated. Dendritic cell (DC) function appears to be rather well managed with age,9focusing attention on T cells. The quality of the immune response is highly dependent on the activation-induced clonal growth of antigen-specific T cells and their differentiation into effector cells. Defects in activation, clonal growth, and differentiation all have the potential to impact the immune response negatively. Due to constant turnover, T cells are at risk for replicative senescence. IL6 antibody Age-dependent erosion of telomeric length in T cell chromosome attests to this cumulative replicative stress.4Defects in proximal T cell receptor signaling have been reported,1012but mostly in mice and in the very elderly. Of all age-dependent effects, changes in T cell development and homeostasis are most striking. Thymic production of new T cells dwindles1315; after the ages of 4050 years, thymic activity in humans is too low to rebuild a T 3-Methylcrotonyl Glycine cell repertoire, and virtually the entire T cell supply is generated 3-Methylcrotonyl Glycine from existing nave and memory T cells.16The lack of influx of new nave T cells can be expected to lead eventually to a progressive loss of nave T cells and contraction of T cell receptor diversity.1721Unexpectedly, CD4 T cell homeostatic mechanisms are very robust, and receptor diversity is maintained well into the seventh decade of life. Between the ages of 70 and 75 years, nave CD4 T cells endure an abrupt and dramatic contraction in diversity, suggesting a period of increased cell death.17The age of 75 appears to be a watershed for human nave CD4 T cells, after which an intact nave T cell compartment no longer exists and nave CD4 T 3-Methylcrotonyl Glycine cell responses are severely compromised. In the current study, we set out to identify early abnormal response patterns in nave CD4 T cells that occur at an age before the system deteriorates. Here, we statement on a novel activation pathway that is selectively affected by age. Nave CD4 T cells from 60- to 75-year-old healthy individuals compared to young adults responded to stimulation with a sustained increase in cytoplasmic zinc. The activation-induced zinc influx resulted in an overexpression of metallothioneins (MT), which increased the cytoplasmic reduction potential and the reservoir of MT-bound zinc. == Materials and Methods == == Subjects == Peripheral blood mononuclear cells were obtained from 98 volunteers, ages 2075 years. The protocol was approved by the Emory University or college Institutional Review Table, and all participants gave informed consent. Individuals with a current or previous history of malignancy or any chronic inflammatory disease, chronic obstructive pulmonary disease, or any poorly controlled disease (advanced atherosclerotic disease, congestive heart failure, diabetes mellitus, hypertension) were excluded. All subjects were fully ambulatory and did not have any evidence of an acute disease at the time of blood draw. == Fluorescence-activated cell sorting analysis == Antibodies utilized for fluorescence-activated cell sorting (FACS) analysis included fluorescein isothiocyanate (FITC)-anti-CD45RA, phycoerythrin (PE)-anti-CD45RO,.
