One representative experiment of three is shown Discussion In this study, we generated an irradiation-induced lymphopenic mouse model. IL-15R expression, respectively. Consistent with these findings, the expression of IL-7R and IL-15R is down- and up-regulated, respectively, in vivo on transferred T-cells in an early phase post T-cell transfer in lymphopenia. We further show that in vitro IL-15 restimulation-induced memory T-cells (compared to IL-2 restimulation-induced effector T-cells) and in vivo transferred T-cells in irradiated IL-15-sufficient C57BL/6 mice (compared to IL-15-deficient IL-15 KO mice) have increased mitochondrial content, but less NADH and lower mitochondrial potential (m), and demonstrate greater phosphorylation of signal transducers and activators of transcription-5 (STAT5) and Unc-51-like kinase-1 (ULK1), and higher expression of B-cell leukemia/lymphoma-2 (Bcl2) and memory-, autophagy- and mitochondrial biogenesis-related molecules. Conclusion Irradiation-induced lymphopenia promotes effector T-cell survival via IL-15 signaling the STAT5/Bcl2 pathway, enhances T-cell memory formation via IL-15 activation of the forkhead-box family of transcription factor (FOXO)/eomesodermin (Eomes) memory and ULK1/autophagy-related gene-7 (ATG7) autophagy pathways, and via IL-15 activation of the mitochondrial remodeling. Our data thus identify some important targets to consider when designing potent adoptive T-cell immunotherapies of cancer. Electronic supplementary material The online version of this article (doi:10.1186/s13578-016-0098-2) contains supplementary material, which is LM22A-4 available to authorized users. represent isotype Ab controls. b Blood samples in WT B6 or irradiated (600 rads) B6 mice (n?=?4) were collected and stained with PE-Kb/OVA I-tetramer (OVA-tetramer), FITC-anti-CD8 Ab (FITC-CD8), and analyzed by flow LM22A-4 cytometry at indicated times after T-cell transfer. The values represent the percentages of OVA-specific CD8+ T-cells in total CD8+ T-cell population. The values in parenthesis represent SD. c Kinetic assessment of transferred CD8+ T-cells in B6 mice irradiated with different doses by cytometry as described in (b). d Western blot analysis. Transferred T-cells were purified from WT B6 and irradiated (600?rads) B6 mice 6?days after T-cell transfer, and lysed for Western blot analysis. Relative expression represents the ratio LM22A-4 of expression of each molecule in cells from irradiated B6 mice versus that in untreated control WT B6 mice. *represent isotype Ab controls. Relative expression represents the ratio of MFI for the expression of each molecule at indicated time points in transferred effector T-cells post T-cell transfer versus that in effector T-cells before T-cell transfer. *represent isotype Ab controls. The percentages of CD62L, IL-7R and KLRG1 positive cells were shown. c IL-2 Te and IL-15 Tm cells (20??106) were adoptively transferred into B6 mice (n?=?4), and blood samples were collected at day 4, day 30, and day 34 [4?days post DCOVA (1??106) boost for recall responses] post T-cell transfer, and analyzed by flow cytometry. The value in each panel represents the percentage of OVA-specific (OVA-tetramer positive) CD8+ T-cells within the total CD8+ T-cell population. d Western blot analysis of IL-2 Te and IL-15 Tm cell lysates using Abs specific for FOXO1, Eomes, T-bet, Bcl-2, pULK1, Atg7, complex-I. Relative expression represents the ratio of the expression of each molecule in IL-15 Tm cells versus that in IL-2 Te cells. e IL-2 Te (represent isotype Ab controls. MFI for expression of each molecule is shown. *represent 5?m. One representative experiment of three is shown Discussion In this study, we generated an irradiation-induced lymphopenic mouse model. To assess a potential effect of lymphopenia on Te cells, we transferred active OT-I CD8+ T-cells into WT B6 or irradiated B6, and demonstrate that irradiation (600?rads)-induced lymphopenia promotes Te cell survival and Tm cell formation. To assess whether IL-7 or IL-15 plays a major role in these effects, we transferred active OT-I CD8+ T-cells into irradiated B6, IL-7 KO and IL-15 KO mice. We demonstrate that transferred T-cells gradually up-regulate IL-7R and IL-15R expression in both WT and irradiated B6 mice, and the prolonged Cav1 survival and enhanced memory are mildly reduced in irradiated IL-7 deficient IL-7 KO mice, consistent with a previous report [20], but dramatically decreased in irradiated IL-15 deficient IL-15 KO mice. Collectively, our results indicate that IL-15 is important for the survival and memory formation of transferred Te cells in lymphopenic mice, in comparison to previously reported IL-7 that plays a critical role in homeostatic proliferation, survival and memory formation of adoptive naive T-cells in lymphopenia [9, 10]. To begin to address why IL-15 figures more prominently than IL-7 in T-cell reprogramming in lymphopenia though both of them are of similar functional effects [21], we first assessed changes in expression of IL-7R and IL-15R on na?ve T-cells or.