title: IL-15 signaling promotes adoptive effector T-cell survival and memory formation in irradiation-induced lymphopenia.
abstract: BACKGROUND
  Lymphopenia 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University, Shanghai, China ; School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Aizhang
authors.initials: A
authors.lastname: Xu
authors.affiliation: Cancer Research Cluster, Saskatchewan Cancer Agency, Saskatoon, SK Canada ; Departments of Oncology, University of Saskatchewan, HSB Room 4D30.1, 107 Wiggins Road, Saskatoon, SK S7N 5E5 Canada.
authors.forename: Kalpana Kalyanasundaram
authors.initials: KK
authors.lastname: Bhanumathy
authors.affiliation: Cancer Research Cluster, Saskatchewan Cancer Agency, Saskatoon, SK Canada.
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.affiliation: Cancer Research Cluster, Saskatchewan Cancer Agency, Saskatoon, SK Canada.
authors.forename: Zhenmin
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Department of Pathology, University of Saskatchewan, Saskatoon, SK Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Freywald
authors.affiliation: Department of Biochemistry, University of Saskatchewan, Saskatoon, SK Canada.
authors.forename: Scot C
authors.initials: SC
authors.lastname: Leary
authors.affiliation: State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University, Shanghai, China ; School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China ; Engineering Research Center of Cell & Therapeutic Antibody, School of Pharmacy, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Rongxiu
authors.initials: R
authors.lastname: Li
authors.affiliation: Cancer Research Cluster, Saskatchewan Cancer Agency, Saskatoon, SK Canada ; Departments of Oncology, University of Saskatchewan, HSB Room 4D30.1, 107 Wiggins Road, Saskatoon, SK S7N 5E5 Canada.
authors.forename: Jim
authors.initials: J
authors.lastname: Xiang
keywords: Autophagy; Effector T-cells; IL-15; Irradiation; Lymphopenia; Mitochondrial biogenesis; T-cell memory; T-cell survival