Age-Related Decline in Activation of JNK by TCR- and CD28-Mediated Signals in Murine T-Lymphocytes

Abstract

c-Jun N-terminal kinase (JNK) is activated when T-lymphocytes are stimulated jointly through the T-cell receptor (TCR) and CD28, and it contributes to T-cell activation and IL-2 production through phosphorylation of transcription factors, including c-Jun. We performed in vitro kinase assays on JNK in CD4+ T-cells, from young and old mice, activated by antibodies to CD3, CD4, and CD28, and found a ∼2-fold decline in JNK activity at the peak of activation, but no significant change in the kinetics of stimulation or in the steady-state expression of JNK. We found a similar decline in c-Jun phosphorylation in stimulated CD4+ T-cells from old mice, suggesting that JNK activation also declined with age in intact cells. Aging does not, however, alter the level of Ras activation by anti-CD3/CD4 ± anti-CD28 or change the level of Ras protein in CD4+ cells, suggesting that the JNK defect is due to changes in the regulation of other upstream regulators. Our results suggest that a decline with age in JNK responses may contribute to the decline in proliferation and IL-2 production seen in CD4+ T-cells from old mice.