Abstract
BackgroundLymphopenia promotes naïve T-cell homeostatic proliferation and adoptive effector T-cell survival and memory formation. IL-7 plays a critical role in homeostatic proliferation, survival and memory formation of naïve T-cells in lymphopenia, and its underlying molecular mechanism has also been well studied. However, the mechanism for adoptively transferred effector T-cell survival and memory formation is not fully understood. Here, we transferred in vitro-activated transgenic OT-I CD8+ effector T-cells into irradiation (600 rads)-induced lymphopenic C57BL/6, IL-7 knockout (KO) and IL-15 KO mice, and investigated the survival and memory formation of transferred T-cells in lymphopenia.ResultsWe demonstrate that transferred T-cells prolong their survival and enhance their memory in lymphopenic mice, in a manner that depends on IL-15 signaling, but not IL-7. We determine that in vitro stimulation of naïve or effector T-cells with IL-7 and IL-15 reduces IL-7Rα, and increases and/or maintains IL-15Rβ expression, respectively. Consistent with these findings, the expression of IL-7Rα and IL-15Rβ 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 (ΔΨm), 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.ConclusionIrradiation-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 materialThe online version of this article (doi:10.1186/s13578-016-0098-2) contains supplementary material, which is available to authorized users.
Highlights
Lymphopenia promotes naïve T-cell homeostatic proliferation and adoptive effector T-cell survival and memory formation
Our work showed that in vitro IL-15 restimulation-induced memory T (Tm) cells and in vivo transferred T-cells in irradiated IL15-sufficient by irradiating C57BL/6 (B6) mice had increased mitochondrial content, but less NADH and lower mitochondrial potential (ΔΨm), and demonstrated 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 (Bcl-2) and memory, autophagy- and mitochondrial biogenesis-related molecules
We demonstrated that transferred T-cells with prolonged survival up-regulated the expression of Bcl-2, FOXO1, Eomes and autophagy-related gene 7 (Atg7) to a greater extent, and enhanced the phosphorylation of STAT5 and ULK1 in irradiated B6 mice expressing IL-15 (Fig. 5a)
Summary
Lymphopenia promotes naïve T-cell homeostatic proliferation and adoptive effector T-cell survival and memory formation. We transferred in vitro-activated transgenic OT-I CD8+ effector T-cells into irradiation (600 rads)-induced lymphopenic C57BL/6, IL-7 knockout (KO) and IL-15 KO mice, and investigated the survival and memory formation of transferred T-cells in lymphopenia. During recovery from T-cell depletion, adoptive naïve T-cells are driven into cell division This process known as homeostatic proliferation, replenishes the T lymphocyte pool [5], and leads to formation of CD44+CD62LhighIL-7R+ memory-like Tm cells [6,7,8]. Our work showed that in vitro IL-15 restimulation-induced Tm cells (compared to IL-2 restimulation-induced effector T-cells) and in vivo transferred T-cells in irradiated IL15-sufficient B6 mice (compared to IL-15 deficient IL-15 KO mice) had increased mitochondrial content, but less NADH and lower mitochondrial potential (ΔΨm), and demonstrated 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 (Bcl-2) and memory-, autophagy- and mitochondrial biogenesis-related molecules. Our data demonstrate that irradiation-induced lymphopenia promotes effector T-cells survival via IL-15 signaling the STAT5/Bcl-2 pathway, and enhances T-cell memory formation via IL-15 activation of the forkhead box (FOXO)/Eomesodermin (Eomes) memory and ULK1/autophagy-related gene 7 (Atg7) autophagy pathways and the mitochondrial remodeling
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