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.
Philosophe
B
B
Boston University School of Medicine, MA.
Miller
R A
RA
D000375:Aging; D000818:Animals; D000937:Antigen-Antibody Reactions; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D000954:Antigens, Surface / Q000032:analysis; D017252:CD3 Complex; D002118:Calcium / Q000502:physiology*; D002469:Cell Separation; D002478:Cells, Cultured; D003208:Concanavalin A / Q000494:pharmacology; D004987:Ethers / Q000494:pharmacology; D005434:Flow Cytometry; D015759:Ionomycin; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000502:physiology*; D018800:Thy-1 Antigens
D000945:Antigens, Differentiation, T-Lymphocyte; D000954:Antigens, Surface; D017252:CD3 Complex; D004987:Ethers; D011948:Receptors, Antigen, T-Cell; D018800:Thy-1 Antigens; D003208:Concanavalin A; D015759:Ionomycin; D002118:Calcium