Molecular mechanism of the impairment in activation signal transduction in CD4(+) T cells from old mice.
It is well known that IL-2 production of CD4(+) T cells from old mice (old T cells) is impaired. In this study, we have examined TCR complex zeta chain expression of old T cells and their TCR downstream signal transduction pathways stimulated with anti-CD3. Activation of protein tyrosine kinases, Fyn and ZAP-70, and turnover of inositol phosphates stimulated with anti-CD3 were severely impaired in old T cells, although levels of these proteins were comparable to those in young T cells. Increase in intracellular Ca2+ concentration in old T cells was also impaired. Old T cells starting the Ca(2+) oscillation by the anti-CD3 stimulation were severely decreased in number and the oscillation waves were broader in shape. T cells with zeta-FcvarepsilonRgamma heterodimer in the TCR-CD3 complex were increased in proportion in old T cells with a concomitant decrease in the T cells with zeta-zeta homodimer. The density of the TCR-CD3 complex on old T cells was confirmed to be comparable to that on young T cells. The impairment in TCR downstream signal transduction pathways and the increase in zeta-FcvarepsilonRgamma heterodimer in the TCR-CD3 complex were confirmed to be the situation in Th1 clones established from old mice. These results indicate that old T cells are impaired in response to TCR stimulation, because T cells with the TCR-CD3 complex containing the zeta-FcvarepsilonRgamma heterodimer are increased in proportion in old T cells.
Tamura
T
T
Department of Allergology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Kunimatsu
T
T
Yee
S T
ST
Igarashi
O
O
Utsuyama
M
M
Tanaka
S
S
Miyazaki
S i
Si
Hirokawa
K
K
Nariuchi
H
H
D000375:Aging / Q000276:immunology*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D020013:Calcium Signaling; D002478:Cells, Cultured; D019281:Dimerization; D005786:Gene Expression Regulation; D007295:Inositol Phosphates / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D008565:Membrane Proteins / Q000737:chemistry / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology; D017455:Receptors, IgE / Q000737:chemistry / Q000276:immunology*; D015398:Signal Transduction / Q000502:physiology*; D051746:ZAP-70 Protein-Tyrosine Kinase
D007295:Inositol Phosphates; D007376:Interleukin-2; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D011948:Receptors, Antigen, T-Cell; D017455:Receptors, IgE; C054979:antigen T cell receptor, zeta chain; D011505:Protein-Tyrosine Kinases; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse