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

• Published in: Experimental gerontology 2002-01, Vol.37 (2), p.359-367
• Main Author: Ponnappan, Usha
• Format: Article
• Language: English
• Subjects: 26S proteasome; Acetylcysteine - analogs & derivatives; Acetylcysteine - pharmacology; Adult; Aged; Aged, 80 and over; Aging; Aging - metabolism; Biomarkers; CD28 Antigens - metabolism; CD3 Complex - metabolism; Chymotrypsin - metabolism; Chymotryptic activity; Cysteine Endopeptidases - metabolism; Cysteine Proteinase Inhibitors - pharmacology; Female; Humans; Immune-dysregulation; Immune-senescence; Leukocyte Common Antigens; Lymphocyte Activation; Male; Multienzyme Complexes - metabolism; Peptide Hydrolases - metabolism; Proteasome Endopeptidase Complex; Receptors, Interleukin-2 - metabolism; Signal Transduction; T lymphocyte subsets; T-Lymphocyte Subsets - metabolism; Ubiquitin - metabolism; Ubiquitin iso-peptidase; Ubiquitin–hydrolase
• ISSN: 0531-5565; 1873-6815
• DOI: 10.1016/S0531-5565(01)00203-0

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, IκB-α 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.