CD28 activation does not down-regulate Cbl-b expression in aged rat T-lymphocytes.

It is well known that T-lymphocyte proliferation declines ex vivo with age, and is associated with decreased expression and/or activity of stimulatory intracellular signaling proteins. However, the role of inhibitory intracellular signaling molecules like the ubiquitin ligase Cbl-b in regulating T-lymphocyte function in aging is largely unknown. Therefore, we tested the hypothesis that T-lymphocyte proliferation declines with age, in part, due to increased expression of Cbl-b. We show that young splenic T-lymphocytes reduced Cbl-b expression when stimulated with anti-CD3 and anti-CD28 antibodies, while in aged T-lymphocytes the CD28-dependent Cbl-b down-regulation did not occur. This effect did not appear to be due to reduced CD28 receptor expression on aged T-lymphocytes. The mechanism for lack of Cbl-b down-regulation may involve the proteasome since blocking proteasomal activity in young T-lymphocytes prevented Cbl-b down regulation while there was no effect in aged T-lymphocytes on Cbl-b expression. These data provide evidence for a novel mechanism by which aging reduces T-lymphocyte function.