This implies the activity of other survival factors on IL-7R– F5 T cells in vivo and
we have previously shown that IL-15 contributes to survival of F5 T cells in the absence of IL-7 2. Therefore, the decline of IL-7R− F5 T cells in dox-free F5 TetIL-7R mice could represent a failure of Buparlisib price these T cells to receive sufficient survival signals in time to prevent their death. Thus, T-cell persistence in vivo is not simply regulated by the presence or absence of survival signalling, but rather is a dynamic process in which cell fitness is constantly tuned by specific environmental cues, of which IL-7 is a key factor. Transcriptional regulation of anti-apoptotic proteins, such as Bcl2 and Mcl1, has long been evoked as a key mechanism of IL-7 activity. In the present study, such regulation of Bcl2 family members was apparent in vivo, in T cells transferred to lymphopenic
hosts, which resulted in substantially upregulated Bcl2 protein levels, and in CD8+ T cells stimulated in vitro with IL-7. Microarray analysis of these T cells revealed a number of transcriptional changes, in addition to Bcl2 upregulation, that could account for their enhanced survival. In both these cases, IL-7 stimulation was non-limiting due to the relatively high cytokine dose employed in vitro and the FDA-approved Drug Library molecular weight lack of host competition in the lymphopenic host environment. In replete F5 mice, where the homeostatic balance has resulted in a peripheral compartment populated with the maximal number of mature T cells possible for that host, IL-7 is available in limiting quantities. Interestingly, our data suggest that under such conditions IL-7
regulates T-cell fitness by mechanisms distinct from those that occur during non-limiting IL-7 signalling. Although the correlation between IL-7Rα and Bcl2 expression in WT thymus implies a regulatory relationship between IL-7 signalling and Bcl2 expression in vivo, our data show this is clearly not the case for naïve T cells. In thymus, very developmental regulation of Bcl2 between DP and SP stages did not depend on IL-7R expression. Conversely, ectopic expression of IL-7Rα in DP thymocytes of dox-fed F5 TetIL-7R mice did not induce Bcl2 expression. Similarly, in peripheral T cells we found that continued IL-7R expression was not required for normal Bcl2 expression in IL-7R– F5 T cells. This was evident both at the protein level, by FACS and Western blot, and at the level of mRNA. Furthermore, wider analysis of many other Bcl2 family members revealed a similar scenario, that mRNA and protein levels were normal in IL-7R– F5 T cells. Although there is evidence that IL-7 regulates Bcl2 expression in activated T cells 3 and early thymic progenitors 18, our data suggest that late developmental and steady state control of Bcl2 expression in naïve T cells is not dependent on IL-7 signalling.
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