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Localization and treatment of an oxidation-sensitive defect within the TCR-coupled signalling pathway that is
G F Weber1, N M Mirza, E J Yunis
1Division of Immunogenetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Abstract:
The age-dependent decline in the ability of T-cells to mount a proliferative response both to mitogens and to receptor ligation is due to an age-related defect in signal transduction, since functional expression of receptors displayed by aged T-cells is not reduced. We show here that, although turnover of phosphatidylinositol is not diminished, total inositol-trisphosphate generation decreases after T-cell receptor (TCR) ligation, resulting in reduced flux of calcium. Defective inositol-trisphosphate generation may result from impaired activation of phospholipase C due to decreased tyrosine phosphorylation of this enzyme after ligation of CD3 in aged cells. Proliferation of aged T-cells, which is normally 10-30% of the level of young controls, was enhanced almost tenfold by glutathione or its precursor N-acetyl L-cysteine (NAC), reached levels of young controls and was accompanied by restoration of normal inositol-trisphosphate generation and calcium flux. These findings suggest that the T-cell antigen receptor is associated with at least two types of signal transduction modules. The first depends on synthesis and phosphorylation of phosphatidylinositol that is independent of sulphydryl groups and is not affected by senescence. The second transduction module includes tyrosine phosphorylation and activation of phospholipase C. This module is regulated by glutathione levels and is diminished in aged T-cells, that are deficient in reducing equivalents which support the PLC gamma-dependent generation of inositol-trisphosphate from phosphatidylinositol derivatives. This underlying biochemical defect also occurs earlier in strains which display premature aging due to differences in the H-2 region of MHC I.
Insights
Aging impairs T-cell proliferation due to reduced signal transduction. Glutathione or NAC supplementation restored T-cell function by enhancing key signaling pathways in aged cells.
Area of Science:
- Immunology
- Cellular Biology
- Biochemistry
Background:
- T-cell proliferation declines with age, impacting immune response.
- This decline is linked to signal transduction defects, not reduced receptor expression.
Purpose of the Study:
- To investigate the molecular mechanisms behind age-related T-cell dysfunction.
- To identify potential interventions to restore T-cell function in aging.
Main Methods:
- Studied T-cell receptor (TCR) signaling in young versus aged T-cells.
- Measured inositol-trisphosphate generation, calcium flux, and cell proliferation.
- Assessed the impact of glutathione and N-acetyl L-cysteine (NAC) on aged T-cells.
Main Results:
- Aged T-cells showed reduced inositol-trisphosphate generation and calcium flux after TCR ligation.
- Defective signaling was linked to impaired phospholipase C activation and reduced tyrosine phosphorylation.
- Glutathione or NAC supplementation significantly enhanced aged T-cell proliferation, normalizing signaling pathways.
Conclusions:
- T-cell signaling involves at least two modules: one unaffected by aging, and another dependent on glutathione levels and tyrosine phosphorylation.
- Reduced glutathione levels in aged T-cells impair a critical signaling module.
- Glutathione or NAC can restore T-cell function in aging, suggesting a therapeutic target.