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PDCD5 regulates iNKT cell terminal maturation and iNKT1 fate decision

Cellular & Molecular Immunology volume 16, pages 746–756 (2019)Cite this article

Abstract

Invariant natural killer T1 (iNKT1) cells are characterized by the preferential expression of T-box transcription factor T-bet (encoded by Tbx21) and the production of cytokine IFN-γ, but the relationship between the developmental process and iNKT1 lineage diversification in the thymus remains elusive. We report in the present study a crucial role of programmed cell death 5 (PDCD5) in iNKT cell terminal maturation and iNKT1 fate determination. Mice with T cell-specific deletion of PDCD5 had decreased numbers of thymic and peripheral iNKT cells with a predominantly immature phenotype and defects in response to α-galactosylceramide. Loss of PDCD5 also selectively abolished the iNKT1 lineage by reducing T-bet expression in iNKT cells at an early thymic developmental stage (before CD44 upregulation). We further demonstrated that TOX2, one of the high mobility group proteins that was highly expressed in iNKT cells at stage 1 and could be stabilized by PDCD5, promoted the permissive histone H3K4me3 modification in the promoter region of Tbx21. These data indicate a pivotal and unique role of PDCD5/TOX2 in iNKT1 lineage determination. They also suggest that the fate of iNKT1 may be programmed at the developmental stage of iNKT cells in the thymus.

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Acknowledgements

The authors wish to thank Yu Zhang (Peking University Health Science Center, China) and Lilin Ye (Army Medical University, China) for kindly providing Bcl2 and Cd4−Cre transgenic mice, Li Bai (University of Science and Technology of China, China) for the DN32.D3 cell line, and Zhongjun Dong (Tsinghua University, China) for the pMSCV-ubc-EGFP and pCL-Eco plasmids. The authors also thank Zhongjun Dong, Xiaoyu Hu (Tsinghua University, China), Yu Zhang, Yanhui Yin, Dan Lv, Chao Zhong, and Wenling Han (Peking University Health Science Center, China) for critical comments, helpful discussions, and critical reagents. The α-galactosylceramide and unloaded and PBS57-loaded CD1d tetramers conjugated to phycoerythrin or allophycocyanin were supplied by the National Institutes of Health tetramer facility. This work was supported by grants from the National Key Research and Development Program of China, 2017YFA0104500 (Q.G.), the National Natural Science Foundation of China, 81471525 and 31671244 (Q.G.), 31470843 (J.Z.),31370898 (Y.C.)  the Foundation for Innovative Research Groups of the National Natural Science Foundation of China, 81621001 (Q.G.), Program for New Century Excellent Talents in University, NCET-13-0018 (J.Z.) and the Fundamental Research Funds for the Central Universities.

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Authors and Affiliations

  1. Key Laboratory of Medical Immunology, Ministry of Health. Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Beijing, China

    Ke Wang, Xinwei Zhang, Yifan Wang, Gaowen Jin, Mingyang Li, Shusong Zhang, Jie Hao, Rong Jin, Jun Zhang, Yingyu Chen & Qing Ge

  2. Peking University Institute of Hematology, People’s Hospital, Beijing, China

    Xiaojun Huang

  3. Peking University Medical and Health Analytical Center, Peking University Health Science Center, Beijing, China

    Hounan Wu

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Contributions

Q.G. and K.W. designed the research, analyzed data, and wrote the manuscript. K.W. performed the research. X.Z., Y.W., S.Z., G.J., and M.L. performed the research. J.H., R.J., and X.H. contributed reagents and technical support. H.W. helped with the flow cytometry. Y.C. and J.Z. edited the manuscript. All authors reviewed the manuscript.

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Correspondence to Jun Zhang, Yingyu Chen or Qing Ge.

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Wang, K., Zhang, X., Wang, Y. et al. PDCD5 regulates iNKT cell terminal maturation and iNKT1 fate decision. Cell Mol Immunol 16, 746–756 (2019). https://doi.org/10.1038/s41423-018-0059-2

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