Localization and treatment of an oxidation-sensitive defect within the TCR-coupled signalling pathway that is associated with normal and premature immunologic aging.
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.
Weber
G F
GF
Division of Immunogenetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Mirza
N M
NM
Yunis
E J
EJ
Dubey
D
D
Cantor
H
H
D019588:Aging, Premature / Q000276:immunology* / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010084:Oxidation-Reduction; D010716:Phosphatidylinositols / Q000378:metabolism; D051966:Phospholipase C gamma; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D010738:Type C Phospholipases / Q000378:metabolism
D000975:Antioxidants; D017252:CD3 Complex; D007527:Isoenzymes; D010716:Phosphatidylinositols; D011948:Receptors, Antigen, T-Cell; D015544:Inositol 1,4,5-Trisphosphate; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D002118:Calcium