A dendritic cell-based systemic vaccine induces long-lived lung-resident memory Th17 cells and ameliorates pulmonary mycosis

Abstract

Tissue-resident memory T cells (TRMs) are a novel nonvascular memory T cell subset. Although CD8+ TRMs are well-characterized, CD4+ TRMs—especially lung-resident memory Th17 cells—are still being defined. In this study, we characterized lung-resident memory Th17 cells (lung TRM17) and their role in protection against the highly virulent fungus Cryptococcus gattii. We found that intravenously transferred DCs preferentially migrated to lungs and attracted recipient DCs and led to the induction of long-lived Th17 cells expressing characteristic markers. This population could be clearly discriminated from circulating T cells by intravascular staining and was not depleted by the immunosuppressive agent FTY720. The C. gattii antigen re-stimulation assay revealed that vaccine-induced lung Th17 cells produced IL-17A but not IFNγ. The DC vaccine significantly increased IL-17A production and suppressed fungal burden in the lungs and improved the survival of mice infected with C. gattii. This protective effect was significantly reduced in the IL-17A knockout (KO) mice, but not in the FTY720-treated mice. The protective effect also coincided with the activation of neutrophils and multinucleated giant cells, and these inflammatory responses were suppressed in the vaccinated IL-17A KO mice. Overall, these data demonstrated that the systemic DC vaccine induced lung TRM17, which played a substantial role in anti-fungal immunity.

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Acknowledgements

This work was supported by KAKENHI (15K21644, 16H05349, and 17K18385) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, by grants from the Japan Agency for Medical Research and Development, AMED, by the Takeda Science Foundation, and by the LEGEND Research Grant Program 2015 from Tomy Digital Biology Co. Ltd. We also thank Drs. Yu Adachi, Taishi Onodera, Yoshimasa Takahashi, and Koji Hayashizaki who provided the technical advice for immunohistochemical analysis.

Author information

K.U. designed the experiments. K.U., M.U., S.S., M.S., S.T., M.A., Y.O. and N.Y. conducted the experiments. K.U. and Y.K. analyzed the data and wrote the article. K.U., K. Shimizu, Y.I., K. Shibuya, Y.M. and Y.K. interpreted the data, and all authors reviewed and approved the manuscript.

Correspondence to Keigo Ueno or Yuki Kinjo.

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The authors declare no competing interests.

Ethical statement:

All animal experiment protocols were approved by the Ethical Committee of the National Institute of Infectious Diseases, Japan (approval numbers 115015, 116019, 116124, 215031, 215036, 215047, 114029, 117032, and 114029) and were performed in accordance with the approved guidelines and regulations.

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