Age-dependent and -independent mechanisms leading to Raf-1 and JNK activation in murine CD4 T lymphocytes.

Aging leads to a decline in the functional capacity of the immune system of both humans and rodents, due in part to diminished T lymphocyte function. Age-related defects in T-cell function are likely to reflect alterations in intracellular signaling pathways activated by the T-cell receptor (TCR) and co-stimulatory surface molecules. We have undertaken studies to determine if kinases involved in the ERK and JNK pathways demonstrate age-sensitive alterations in their activation. We find that activation of Raf-1, a kinase involved in the ERK pathway, is diminished in TCR stimulated CD4+ T-cells from older donors, and that the effect of age is not dependent on either a change in kinetics or a decline in the total amount of Raf-1 Protein per cell. The co-stimulatory molecule CD28 can also activate Raf-1 in a TCR-independent manner. However, aging does not significantly alter Raf-1 activation in response to CD28 stimulation, either alone or in conjuction with TCR stimulation. In contrast to Raf-1, c-Jun NH2 terminal kinase (JNK) requires simultaneous stimulation of both the TCR and CD28 for activation in T-cells. There is an age-dependent decline in JNK activation by the TCR + CD28 without alterations in protein levels or stimulation kinetics. The decline in both Raf-1 and JNK activity is caused by two age-dependent phenomena: an increase with age in hyporesponsive memory cells and a decrease in kinase activity in naive cells from old mice. JNK is also activated by stress agents, such as osmotic shock, UV light and H2O2, some of which utilize alternate pathways other than those used by TCR + CD28 signals. The induction of JNK function by osmotic shock and H2O2 does not change with age while UV induction is age-sensitive. Interestingly, TCR driven activation of the G-protein p21 Ras, thought to play a role in both Raf-1 and JNK activation, is unaffected by age suggesting that the function of other Raf-1 and JNK regulators is altered in aged mice. Taken together, our data suggest that, in T cells, downstream signaling events such as the ERK and JNK pathways are activated by multiple regulatory pathways, some of which display age-sensitive activities.PhDBiological SciencesCellular biologyHealth and Environmental SciencesImmunologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/131695/2/9929868.pd