Ubiquitin-proteasome pathway is compromised in CD45RO+ and CD45RA+ T lymphocyte subsets during aging.

Recent reports from our laboratory have demonstrated that CD45RO+ and CD45RA+ T lymphocytes from the elderly are compromised in their response to activation-induced IL-2 receptor expression, IkappaB-alpha degradation, as well as nuclear translocation of NFkB. To understand the basis of this activation-induced dysfunction in the elderly, we have examined the role of the ubiquitin-proteasome pathway. Our results demonstrate that both CD45RO+ and CD45RA+ T lymphocytes from the elderly show significant reduction in the constitutive 26S proteasome-associated chymotryptic activity, when compared to those in the young. Additionally, anti-CD3-CD28 treatment induced enhancement of proteasome-associated enzymatic activity in cells from the young, but not in cells from the elderly. Lowered proteasome-associated activity and its effect on reduced immune responses in the elderly could be mimicked by experiments which involved pretreatment of T cells from young donors with a proteasome specific inhibitor, lactacystin. These data demonstrate that IL-2 receptor induction is clearly compromised in T cells from the young when proteasomes are inhibited by pretreatment with lactacystin. An examination of ubiquitin specific hydrolase activity, demonstrated a decrease in activated CD45RA+ and CD45RO+ T cell subsets from the elderly when compared to young. These results suggest that lowered proteasome-associated enzymatic activity in combination with compromised de-ubiquitinating activity may be responsible for lowered activation-induced NFkB and NFkB-mediated gene expression in elderly subjects.