Int J Med Sci 2017; 14(10):977-983. doi:10.7150/ijms.20212

Research Paper

IL-12 Influence mTOR to Modulate CD8+ T Cells Differentiation through T-bet and Eomesodermin in Response to Invasive Pulmonary Aspergillosis

Hao Wang1, Jingdong Li2, Qiyang Han3, Fei Yang4, Yu Xiao5, Meng Xiao6, Yingchun Xu6, Longxiang Su1, Na Cui1✉, Dawei Liu1✉

1. Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, China;
2. Department of Critical Care Medicine, 4 th Peoples' Hospital of Shenyang, Liaoning Province, China;
3. Department of Critical Care Medicine, Dalizhou People's Hospital, Yunnan Province, China;
4. Department of Critical Care Medicine, Chifeng City Hospital, Inner Mongolia, China;
5. Department of Pathology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science;
6. Department of Clinical Laboratory, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science.

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Citation:
Wang H, Li J, Han Q, Yang F, Xiao Y, Xiao M, Xu Y, Su L, Cui N, Liu D. IL-12 Influence mTOR to Modulate CD8+ T Cells Differentiation through T-bet and Eomesodermin in Response to Invasive Pulmonary Aspergillosis. Int J Med Sci 2017; 14(10):977-983. doi:10.7150/ijms.20212. Available from http://www.medsci.org/v14p0977.htm

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Abstract

Objective: To investigate whether mTOR signaling pathway regulate the proliferation and differentiation of CD8+ T cells by transcription factors T-bet and Eomes, and explore the role of IL-12 in this biological procedure.

Methods: Aspergillus fumigatus spore suspension nasal inhalation was used to establish the invasive pulmonary aspergillosis (IPA) mouse model. After inoculation, rapamycin (2mg/kg) each day or IL-12 (5ug/kg) every other day was given for 7 days. The blood samples were obtained before the mice sacrificed and lung specimens were taken. Pathological sections were stained with hematoxylin and eosin (HE). The number of CD8+effective memory T cells (Tem) and the expression of IFN-γ, mTOR, ribosomal protein S6 kinase (S6K), T-bet and EOMES were measured by flow cytometry. The levels of IL-6, IL-10 and Galactomannan (GM) were determined by ELISA.

Results: After IL-12 treatment, the number of CD8+ Tem and the expression of IFN-γ increased significantly; while quite the opposite results were observed when the mTOR pathway was blocked by rapamycin. The expression of mTOR and S6K as well as the level of IFN-γ of the IL-12 treatment group were significantly higher than those in IPA and IPA + rapamycin groups. In addition, IL-12 promoted increasing T-bet and down regulating Eomes to make the Tem transformation. The final immune effector was high level of inflammatory cytokines (IL-6) and low level of anti-inflammatory factors (IL-10) and this strengthened immune response to the Aspergillus infection.

Conclusions: The biological effects of Tem could significantly affect IPA infection host immune regulation, which depended on the activation of mTOR signaling pathway by IL-12.

Keywords: IL-12, Mammalian target of rapamycin (mTOR), CD8+effect memory T cells (Tem), Invasive Pulmonary Aspergillosis (IPA).