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Transgenic Mouse Models for Immunosenescence

[ Vol. 4 , Issue. 5 ]


Izumi Nakashima, Jun Du, Toshihiro Yokoyama, Yoshiyuki Kawamoto, Kozo Ohkusu-Tsukada and Ken-ichi Isobe   Pages 435 - 443 ( 9 )


Ageing-dependent dysfunctions develop for each of various cell types in living organisms. Amongst them, immunosenescence, an ageing-dependent deterioration of the immune system, seriously affects the health condition of an aged individual. The central problem in immunosenescence is a decrease in the ability of T-cells to respond to antigens for proliferation and cytokine production, accompanied by accumulation of T-cells with a memory cell phenotype (CD44-high CD45RB-low) replacing those with a naïve cell phenotype (CD44-low CD45RB-high). Recently, a transgenic mouse model and a genetically modified mouse model have been reported to display promoted immunosenescence. One is a mouse line transgenic to human CD2 promoter / enhancer-guided rabbit protein kinase C(PKC)α, and the other is a mouse line in which the p53 gene is deficient (p53- / -). Both of these mouse lines display accelerated accumulation of memory Tcell replacing naïve T-cells during ageing, accompanying progressively diminishing responsiveness to sheep red blood cell antigens for cytokine production. T-cells activate PKCα when they receive either an antigenic or stress stimulus. Repetitions of antigenic and stress stimuli that recurrently activate PKCα are probably mimicked by continuously elevated PKCα activity in the PKCα transgenic mice. Activated PKC-α probably counteracts the apoptosis-inducing signal, which prevents activation-induced cell death of T-cells and causes accumulation of memory T-cells as the descendants of activated T-cells that have survived. On the other hand, p53 is known to mediate the signaling for apoptosis induction that follows DNA damage due to oxidative stress. The apoptotic signal pathway fails to work well in p53- / - mice. During ageing of these mice, T-cells must encounter a number of antigenic and stress stimuli for activation, and activation of Tcells that is not followed by cell-death causes accumulation of memory T-cells. Results of experiments using the two transgenic mouse models for immunosenescence introduced here support the view that immunosenescence develops by chronic exposure to antigenic and stress stimuli, which is promoted by a defect in the mechanism for efficient elimination of activated T-cells.


transgenic mouse models, Immunosenescence, cytokine production, memory cell phenotype, naive cell phenotype, memory t-cells, stress stimuli


Department of Immunology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showaku,Nagoya 466-8550, Japan.

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