Thus, IL-7 must be controlling naïve T-cell survival by mechanisms other than simply regulating expression level of Bcl2 family members. Taken together, our data
strongly suggest that IL-7 controls homeostatic fitness of T cells in replete hosts by non-transcriptional mechanisms. IL-7 can activate PI3K 23, 37 and downstream Akt/PKB whose kinase activity can potentially modulate multiple pathways and that could constitute such non-transcriptional mechanisms. Consistent with this view, IL-7 has been reported to prevent apoptosis in IL-7 responsive cell lines by inhibiting Bad activity following Small molecule library Akt/PKB phosphorylation of Bad 31. However, using F5 T cells over-expressing Bad, we could find no evidence that Bad was regulating naïve T-cell fitness in vitro, or in vivo in a range of homeostatic environments or in the absence of IL-7 signalling altogether. This is also consistent with experiments showing that inhibition of PI3K does not block the
pro-survival properties Imatinib ic50 of IL-7 23 in vitro. However, in vitro, any potential pro-apoptotic consequence of PI3K blockade may be masked by the effects of upregulation of Bcl2 expression by IL-7. Furthermore, it is unclear whether or to what extent IL-7 activates PI3K in naïve T cells in vivo. Thus, it is not possible to exclude a potential pro-survival role for IL-7-dependent PI3K activation in vivo. The non-transcriptional mechanisms by which IL-7 promotes T-cell survival in vivo remain obscure. However, since we observed no differences in abundance of key Bcl2 family members in IL-7R− F5 T cells, it seems likely that regulation at the level of sub-cellular localization of pro- or
anti-apoptotic proteins and/or their interaction with one another may rather account for the perturbed mitochondrial homeostasis we observed in IL-7R− F5 T cells. Furthermore, another study suggests that posttranslational regulation of glucose transporters may be involved 36. In conclusion, we show for the first time that homeostatic fitness of T cells is dynamically regulated by IL-7, involving multiple mechanisms that differ between lymphoreplete and lymphopenic conditions. Molecular motor The view that T-cell fitness is not a digital state of either survival or death but rather dynamic state is consistent with concepts of competition for survival resources. Such a view is also consistent with the recent insights into the high mobility of lymphocytes within the 3-dimensional structure of the lymph node 38, 39, and that the source of IL-7, and likely other survival factors within these structures, is not homogeneously distributed, but rather focal and from specific cell types 11. In such a context, a dynamic fitness model of T-cell survival would permit integration and interpretation of multiple and likely sporadic survival cues.