Differential effects of STAT5 and PI3K/AKT signaling on effector and memory CD8 T-cell survival

Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2010; 107(38):16601-6. DOI: 10.1073/pnas.1003457107
Source: PubMed


During viral infection, effector CD8 T cells contract to form a population of protective memory cells that is maintained by IL-7 and IL-15. The mechanisms that control effector cell death during infection are poorly understood. We investigated how short- and long-lived antiviral CD8 T cells differentially used the survival and cell growth pathways PI3K/AKT and JAK/STAT5. In response to IL-15, long-lived memory precursor cells activated AKT significantly better than short-lived effector cells. However, constitutive AKT activation did not enhance memory CD8 T-cell survival but rather repressed IL-7 and IL-15 receptor expression, STAT5 phosphorylation, and BCL2 expression. Conversely, constitutive STAT5 activation profoundly enhanced effector and memory CD8 T-cell survival and augmented homeostatic proliferation, AKT activation, and BCL2 expression. Taken together, these data illustrate that effector and memory cell viability depends on properly balanced PI3K/AKT signaling and the maintenance of STAT5 signaling.

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Available from: Susan M Kaech, Jul 07, 2014
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    • "However, the pertinent signaling pathways that underlie the recovery of T cell responses by PD-1:PD-L1 blockade in vivo are not known; such information could offer important insights into the etiology of CTL exhaustion and might also provide a basis for the development of therapies for treating chronic diseases. Although signaling through PI3K, AKT, and mTOR enhances effector CTL differentiation, it suppresses the differentiation and maturation of memory CTLs (Araki et al., 2009; Hand et al., 2010; Kim et al., 2012; Pearce et al., 2009; Rao et al., 2010). This occurs, in part, because AKT phosphorylation inhibits the nuclear activity of FoxO transcription factors, namely FoxO1, which positively regulates several genes involved in naive and memory T cell survival and trafficking including Il7ra, Ccr7, Klf2, Sell (CD62L), Tcf7, Eomes, and Bcl2 (Kerdiles et al., 2009, 2010; Kim et al., 2012, 2013; Hess Michelini et al., 2013; Ouyang et al., 2009, 2010, 2012; Rao et al., 2012; Sullivan et al., 2012a, 2012b; Tejera et al., 2013). "
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