Protein kinase C alpha-mediated chronic signal transduction for immunosenescence.
In CD2/protein kinase C alpha (PKC alpha)-overexpressing human CD2/rabbit PKC alpha transgenic mice, an aging-dependent increase in PKC alpha expression and a decrease in proliferative responsiveness of splenic T cells were promoted. We found that an aging-associated accumulation of CD44(high) CD45RB(low) memory CD4+ T cells in exchange for CD44(low) CD45RB(high) naive CD4+ T cells was promoted in transgenic mice. A disequilibrium between Ag-dependent generation and subsequent elimination of memory T cells in these mice was shown to underlie this phenomenon. When stimulated with Ag, the PKC alpha transgenic mice responded poorly regarding Ab production and produced cytokines biased for high IFN-gamma/IL-12 and low IL-4/IL-10 levels. These results prove, for the first time, a causal role for chronic signal transduction through PKC alpha in aging-associated immunodysfunction and provide the first animal model for genetically promoted immunosenescence.
Ohkusu
K
K
Department of Immunology, Nagoya University School of Medicine, Japan.
Du
J
J
Isobe
K I
KI
Yi
H
H
Akhand
A A
AA
Kato
M
M
Suzuki
H
H
Hidaka
H
H
Nakashima
I
I
D000375:Aging / Q000235:genetics / Q000276:immunology*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000201:enzymology / Q000276:immunology; D002455:Cell Division; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004790:Enzyme Induction; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D007153:Immunologic Deficiency Syndromes / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology*; D017493:Leukocyte Common Antigens / Q000032:analysis; D051379:Mice; D008822:Mice, Transgenic; D011493:Protein Kinase C / Q000235:genetics / Q000502:physiology*; D051571:Protein Kinase C-alpha; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000166:cytology
D016207:Cytokines; D018960:Hyaluronan Receptors; D007527:Isoenzymes; D011993:Recombinant Fusion Proteins; C496628:PRKCA protein, human; C496630:Prkca protein, mouse; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D017493:Leukocyte Common Antigens