Inhibition of Fas-mediated apoptotic cell death of murine T lymphocytes in a mouse model of immunosenescence in linkage to deterioration in cell membrane raft function.
We previously developed a transgenic mouse line into which a rabbit protein kinase Calpha (PKCalpha) gene fused to a human CD2 promoter/enhancer was introduced, and we found that immunosenescence was facilitated in these transgenic mice. In this study, we found that along with age-dependent increase in the level of protein expression of PKCalpha and its translocation to the membrane, activated T cells became less sensitive to apoptosis-inducing anti-Fas antibody. The capacity of T cells to express Fas antigen on their surfaces in response to anti-CD3 and interleukin-2 was impaired in PKCalpha-transgenic mice of relatively advanced age, although background Fas expression levels on T cells from those mice were high. We then found that out of proportion to a high level of cell surface Fas expression the density of cholera toxin B (CTx)-binding raft elements decreased in PKCalpha-transgenic mice of relatively advanced age and to a lesser extent in normal mice of advanced age. Correspondingly, the expression level of raft-associating Lck was decreased in these mice. These findings suggest for the first time that immunosenescence of T cells involves a decrease in density of cell surface CTx-binding raft elements, which might underlie a deterioration in T-cell signal pathway for either cell death or cell activation.
Yokoyama
Toshihiro
T
Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Du
Jun
J
Kawamoto
Yoshiyuki
Y
Suzuki
Haruhiko
H
Nakashima
Izumi
I
D000375:Aging / Q000276:immunology*; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D002478:Cells, Cultured; D002772:Cholera Toxin / Q000378:metabolism; D004195:Disease Models, Animal; D007108:Immune Tolerance / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D021962:Membrane Microdomains / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011493:Protein Kinase C / Q000235:genetics / Q000276:immunology; D051571:Protein Kinase C-alpha; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D019014:fas Receptor / Q000276:immunology*
D007376:Interleukin-2; D019014:fas Receptor; D002772:Cholera Toxin; C496630:Prkca protein, mouse; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha