Redox regulation of the proteasome in T lymphocytes during aging

Abstract

Proteasome is a major cellular organelle responsible for the regulated turn-over of both normal and misfolded proteins. Recent reports from our laboratory have implicated lowered proteasomal chymotryptic activity to be responsible for decreased induction of the transcription factor NFκB in T lymphocytes during aging. In this study, we have further analyzed the basis for this decline in proteasomal function, by focusing on the role of oxidative stress. Upon exposure to the pro-oxidant BSO, both ATP-stimulatable 26S, as well as ATP-independent 20S proteasomal catalytic activity could be down-regulated in T cells from young donors, mimicking the decline observed in T cells from the elderly. Loss in these catalytic activities, following exposure to pro-oxidant stimulus also resulted in a decline in both activation-induced proliferation as well as degradation of the inhibitor IκBα, with concomitant increase in the accumulation of carbonylated proteins, mimicking responses seen in T cells from the elderly. Pretreatment with an antioxidant, NAC could override pro-oxidantmediated, but not age-associated decrease in both 20S proteasomal activities. These results suggest that the decrease in proteasomal activities observed during aging may be secondary to oxidative stress and underlie immune senescence.

Aging and Immune Function: Molecular Mechanisms to Interventions

“…Our recent studies delineating this paradox in aging have provided some mechanistic insight into the role of 26S proteasomal defects in NFkB -mediated pro-inflammatory cytokine induction during aging (66). Clearly, our studies and those of others have implicated a central role for the 26S proteasome in T cell functional response in the elderly (71,294). Recent studies in flies, mice, and our own studies on human T cells ex vivo in culture indicate that restoration of proteome maintenance genes and antioxidant response element (ARE) activators, such as nuclear factor erythroid-2-related factor 2 (Nrf2) modulators, may be beneficial in retarding or restoring functional activity (199,364) (unpublished data from our laboratory).…”

“…Studies in mice have demonstrated that age-related decline in signaling events starts at the membrane, with decreased recruitment of TCR associated signaling molecules to the immunological synapse, the site of activation cluster (89). While such direct evidence for lowered signaling at the synapse during aging is lacking in human T cells, T cells exposed to oxidative stress manifest reduction in signaling, leading to lowered IL-2 production (71,98). The decline in IL-2 production has been attributed to be one of the major factors underlying immune decline in T cell functional response (141,370).…”

“…However, to this date, it is unclear whether increased ROS is the cause or a consequence of aging, and the debate still rages on. More recently, however, it has come to be appreciated that not all ROS are deleterious, and a gradation of ROS induction occurs, with smaller and milder amounts acting as a mediator in cellular signaling, and excess or imbalance resulting in deleterious effects (58, 71,157,237,279,374). Corroborating this idea, recent evidence suggests that hematopoietic stem cells and early progenitors contain lower levels of ROS than their more differentiated progeny, and that these may be critical in maintaining their ''stemcell-ness,'' or stem cell potential (82).…”

“…Thus, both the more differentiated effector cells and the naive stem cells appear to share a common principle, that is, ROS induction in the context of cellular signaling, but clearly differ in the extent or magnitude of ROS induction. Increasingly, age-associated accumulation of ROS appears to be attributable to an imbalance between the free radical generation and antioxidant defenses induced by the phase-II enzymes, with an increase in the former and a concomitant decline in the latter (71,199). This accumulation of ROS during aging accounts for the generation of oxidatively modified proteins and DNA.…”

Peroxiredoxin II Regulates Effector and Secondary Memory CD8+T Cell Responses

“…Together, these findings suggest that ROI generated in response to receptor stimula-tion are positive mediators of lymphocyte activation. In contrast, high levels of ROI have been implicated with T cell dysfunction in diseases such as cancer, HIV, and systemic lupus erythematosus and in aging (7,13,25,40). Therefore, maintaining optimal levels of ROI is critical to T cell proliferation and function.…”