beta-adrenoceptor blockade alters thymocyte differentiation in aged mice

The thymus is the primary site for generation of naive T-lymphocytes in the young animal. With age, the thymus progressively involutes and fewer matur e T-cells are produced and migrate to the periphery. With thymic involution , increased density of sympathetic noradrenergic (NA) innervation and conce ntration of norepinephrine (NE) have been observed. To determine if the age -related changes in thymocyte differentiation are modified by NE signaling through beta -adrenergic receptors, 2-month (mo) and 18-mo old BALB/c mice were implanted subcutaneously with pellets containing the non-selective bet a -adrenoceptor antagonist nadolol. Four and one-half weeks later, thymus a nd peripheral blood were collected to assess changes in thymocyte different iation and naive T-cell output by flow cytometric analysis of T-cell subpop ulations. In old mice, but not in young mice, thymocyte CD4/CD8 co-expressi on was altered by beta -adrenoceptor blockade. In nadolol-treated old mice, the frequency of the immature CD4(-)8(-) population was increased, and the intermediate CD4(+)8(+) population was reduced. A corresponding increase i n the frequency of mature CD4(-)8(+), but not CD4(+)8(-) cells was observed . The increase in CD4-8+ cells is most likely not mediated by more CD4(+)8( +) cells undergoing positive selection, because CD3(hi) expression in the C D4(+)8(+) population was not altered by nadolol. The percentage of CD8(+)44 (low) naive cells in peripheral blood increased in nadolol-treated mice, su ggesting that more CD4(-)8(+) cells were exported from the thymus to the pe riphery. These results indicate that the age-associated increase in sympath etic NA innervation of the thymus modulates thymocyte maturation. Pharmacol ogical manipulation of NA innervation may provide a novel means of increasi ng naive T-cell output and improving T-cell reactivity to novel antigens wi th age.