T lymphocyte heterogeneity in old and young mice: functional defects in T cells selected for poor calcium signal generation

An increase in cytoplasmic free calcium ion concentration is thought to play a critical role in the entry of resting T lymphocytes into the mitotic cycle. Not all murine T cells, however, generate such a calcium signal when exposed to mitogenic doses of concanavalin A (Con A), and the proportion of nonresponsive cells increases with age in adult mice. Since the frequency of T cells able to generate cytotoxic or lymphokine‐secreting cells in culture also declines in old age, we have speculated that the defect in changes in Ca²⁺ concentration might underlie this functional deficit. To examine the relationship between functional competence and the calcium signaling pathway, we performed limiting dilution analyses of T cells enriched (by a fluorescence‐based cell‐sorting method) for high or low calcium signal generation. We found that rapid Ca²⁺ signal generation after Con A exposure did indeed correlate well with functional competence in Con A‐stimulated limiting dilution cultures. Furthermore, selection for Ca²⁺ signals induced by anti‐CD3 antibody, or even by ionomycin, similarly enriched for the functionally competent set of T cells. The ionomycin result, in particular, suggests that the difference between the reactive and nonreactive sets of T cells is unlikely to result simply from alterations in receptor‐linked signal transduction pathways. We discuss a model in which immune senescence involves an age‐dependent increase in a subset of T cells in which changes in cytoplasmic Ca²⁺ concentration are relatively difficult to induce by either receptor‐dependent mitogens or ionophores.