Montag, David T.

Degeneration of the thymus and severe contraction of the T‐cell repertoire with aging suggest that immune homeostasis in old age could be mediated by distinct effectors. Therefore we examined receptors expressed on T cells as they undergo senescence in vitro , and those displayed by circulating T cells during normal chronologic aging. Monitoring of T cells driven to senescence showed de novo induction of CD56, the prototypic receptor of NK cells. Analysis of fresh T cells in blood showed an age‐dependent induction of CD56. These unusual T cells expressed high levels of Bcl2, p16, and p53, and had limited, or completely lost, ability to undergo cell division; properties consistent with senescence. CD56 cross‐linking without TCR ligation on CD56 + T cells resulted in extensive protein phosphorylation, NFκB activation, and Bax down‐regulation. CD56 cross‐linking was also sufficient to drive production of various humoral factors. These data indicate that the immunologic environment in old age is functionally distinct, rather than a dysfunctional version of that seen at a young age. In view of the reported inefficiencies of TCR‐driven immunity with aging, elicitation of TCR‐independent immune cascades by CD56 + T cells provide new avenues for the development of alternative strategies to enhance protective immunity in the elderly. [Supported by NIH grants R01‐AG022379, R01‐AG023629, P20‐CA103730, and T35‐AG026778].

Abstract Degeneration of the thymus and severe contraction of the T cell repertoire with aging suggest that immune homeostasis in old age could be mediated by distinct effectors. Therefore, receptors expressed on T cells as they undergo senescence in vitro, as well as those displayed by circulating T cells during normal chronologic aging, were examined. Monitoring of T cells driven to senescence showed de novo induction of CD56, the prototypic receptor of NK cells. Analysis of fresh T cells in peripheral blood showed an age-dependent induction of CD56. These unusual T cells expressed high levels of Bcl2, p16, and p53, and had limited, or completely lost, ability to undergo cell division, properties consistent with senescence. CD56 cross-linking without TCR ligation on CD56+ T cells resulted in extensive protein phosphorylation, NF-κB activation, and Bax down-regulation. CD56 cross-linking was also sufficient to drive production of various humoral factors. These data suggest that the immunologic environment in old age is functionally distinct, rather than being a dysfunctional version of that seen at a young age. CD56+ T cells are unique effectors capable of mediating TCR-independent immune cascades that could be harnessed to enhance protective immunity in the elderly.