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

Abstract

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.

T Cell Rewiring in Differentiation and Disease

“…For example, we found that mouse memory CD4 T cells are remarkably deficient in SLP-76 expression, although the related linker/adapter LAT is expressed in comparable levels in naive and memory T cells (54). The memory T cell-specific decrease in SLP-76 is consistent with the decreased calcium responses and IL-2 production previously identified in memoryphenotype CD4 T cells (71)(72)(73)(74), and also found in SLP-76-deficient Jurkat T cells (75). Whether a dampening of signals controlled by decreasing SLP-76 expression facilitates memory generation from effector cells, or whether memory cell signaling dampening results from their long-term maintenance and/or homeostasis remains to be established.…”

Increased Mortality and Impaired Clonal Deletion After Staphylococcal Enterotoxin B Injection in Old Mice: Relation to Cytokines and Nitric Oxide Production

“…This suggests that in the elderly various other factors may contribute to determine cell death. Amongst these, lower PTK activities [12,13], shown to be involved in DNA fragmentation [55], modifications of proteins involved in cell death, and imbalance of cytokine production as we showed here, may antagonize the apoptosis inducing effect of IFN-g. Further investigations are needed to elucidate how these different factors relate to each other.…”

“…Humoral immunity has been found to be changed as well: antibodies produced by aged individuals display a lower affinity and are less protective than antibodies from young individuals [5]. Other agerelated modifications include an imbalance in cytokine profiles [6][7][8][9][10], production of hormones [11], and defective signal transduction pathways due to the impairment of Ca 2þ mobilization and the activation of protein kinases [12,13]. In addition, the involution of the thymus [14] may also have a role in this process as the output of new T cell emigrants declines considerably with age resulting in an accumulation of memory T cells [15][16][17].…”

Altered Composition of the Immunological Synapse in an Anergic, Age-Dependent Memory T Cell Subset

“…Aging leads to a decline in the proportion of CD4 T cells that exhibit intracellular changes in Ca 2ϩ concentration (35,36), reflecting at least in part the relative unresponsiveness of cells in the P-gp high pool (9). Increases in cytosolic Ca 2ϩ after TCR stimulation appear to depend upon LAT (21,22).…”