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Are senescence and exhaustion intertwined or unrelated processes that compromise immunity?


Can the immune system be reactivated continuously throughout the lifetime of an organism or is there a finite point at which repeated antigenic challenge leads to the loss of lymphocyte function or the cells themselves or both? Replicative senescence and exhaustion are processes that control T cell proliferative activity and function; however, there is considerable confusion over the relationship between these two intrinsic cellular control mechanisms. In this Opinion article, we compare the molecular regulation of senescence and exhaustion in T cells. Available data suggest that both processes are regulated independently of each other and that it may be safer to block exhaustion than senescence to enhance immunity.

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Figure 1: The three phases of senescence induction.
Figure 2: A hypothetical scheme for the induction of proliferative exhaustion by inhibitory receptor signalling.
Figure 3: A putative scheme suggesting that senescence and exhaustion pathways block T cell proliferation by distinct mechanisms.


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Work leading to this Review was funded by the British Biotechnology and Biological Sciences Research Council and the Wellcome Trust ViP Scheme. We also wish to thank numerous colleagues for extensive discussions that helped in the production of this article.

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Correspondence to Arne N. Akbar.

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Akbar, A., Henson, S. Are senescence and exhaustion intertwined or unrelated processes that compromise immunity?. Nat Rev Immunol 11, 289–295 (2011).

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