Low-grade inflammation with aging has consequences for T-lymphocyte signaling.

T lymphocytes are key players of immune responses that are associated with immune senescence because their functions are the most affected with aging. Defects in signal delivery to the nucleus have been demonstrated, by our group and others, in human aging and may explain the dysfunctions that occur in T cells with aging. Although aging has been related to a decline in several biological functions, it is also associated with a basal low-grade proinflammatory state and an increase in oxidative stress that lead to changes and damage. However, there are no clear data concerning the basal state of activation of T lymphocytes and its putative link with the low-grade inflammation observed with aging. Since membrane microdomains (lipid rafts) are specialized plasma membrane structures involved in T-lymphocyte activation, we studied the effect of aging on the phosphorylation state of signaling molecules associated with lipid rafts. We found that the signaling molecules in T lymphocytes from elderly donors were hyperphosphorylated and that the high basal state of phosphorylation did not allow activation exposure to a T-cell stimulus. We found that the cholesterol composition is changed in lipid rafts of resting T cells. We analyzed lipid raft distribution in situ using confocal microscopy and found a disorganization of these microdomains in T cells from aged donors. In conclusion, we show a link between aging, T-lymphocyte lipid rafts, immune senescence, and low-grade inflammation.