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Ets1 regulates the differentiation and function of iNKT cells through both Pointed domain-dependent and domain-independent mechanisms

Cellular & Molecular Immunology volume 17, pages 1198–1200 (2020)Cite this article

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The transcription factor Ets1 is essential for the development of invariant natural killer T (iNKT) cells; however, its detailed role and mechanism of action are unknown. Here, we show that Ets1 is dispensable for CD1d-mediated selection, but is essential for subsequent differentiation of post-selected iNKT cells. This function is partly compensated by forced expression of a transgenic Vα14 Jα18 TCR and is independent of its N-terminal Pointed (PNT) domain. Ets1 is also required for optimal expression of cytokines by differentiated iNKT1 and iNKT2 cells, but inhibits the differentiation/function of iNKT17 in vitro and in vivo. These functions, however, depend on the PNT domain. Taken together, our results indicate that Ets1 regulates the differentiation/function of iNKT cells at multiple steps through both PNT domain-dependent and PNT domain-independent mechanisms.

The PNT domain of Ets1 serves as a protein-interacting domain4. Interaction with other proteins through the PNT domain critically influences the function of Ets1 in many in vitro systems5,6,7. It is unknown whether the PNT domain is required for Ets1 to regulate the differentiation and function of iNKT cells. We therefore created a mouse strain (FFcre) expressing Ets1 lacking the PNT domain (amino acid residues 28–134) in a T cell-specific manner (Supplementary Fig. 2a). The level of the truncated protein, called PNTless Ets1, in FFcre thymocytes was comparable to that of the full-length Ets1 in control cells (FF) (Supplementary Fig. 2b). FFcre mice were born according to the Mendelian ratio and were grossly healthy up to at least 6 months of age.

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Acknowledgements

We thank Dr. Ming-Zong Lai and Dr. Patrick Brenner for critical review of this manuscript. We acknowledge the NIH Tetramer Core Facilities (contract HHSN272201300006C) for the provision of CD1d tetramers. We also acknowledge the service provided by the Third Core Lab and the Flow Cytometric Analyzing and Sorting Core Facility and the English editing provided by the Department of Medical Research at National Taiwan University Hospital. This work is supported by grants from the United States Department of Defense (W81XWH-11-1-0492 to I.-C.H.); the National Institutes of Health (AR070171 to I.-C.H. and HL082717 to P.O.); the Ministry of Science and Technology (103-2311-B-650-001 and 105-2311-B-214-002 to T.-S.T.), Taiwan; and E-Da Hospital (103-EDN16, 104-EDN12, 105-EDN07, and EDAHI105002 to T.-S.T.), Taiwan.

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Authors and Affiliations

  1. Department of Medical Research, E-Da Hospital, I-Shou University, Kaohsiung, Taipei, China

    Tzong-Shyuan Tai

  2. Department of Medicine, Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, MA, USA

    Hsiao-Wei Tsao & I-Cheng Ho

  3. Harvard Medical School, Boston, MA, USA

    Hsiao-Wei Tsao, Peter Oettgen & I-Cheng Ho

  4. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA

    Hsiao-Wei Tsao

  5. Department of Medical Research, National Taiwan University Hospital, Taipei, 10002, China

    Wan-Chu Chuang, Chih-Chun Liu, Yu-Wen Huang & Ya-Ting Chuang

  6. Department of Medicine, Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA, USA

    Peter Oettgen

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  1. Tzong-Shyuan Tai
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Contributions

T.-S.T. designed the study, performed most experiments, analyzed data, and co-wrote the manuscript. Y.-T.C. performed the experiments, analyzed the data, and co-wrote the manuscript. H.-W.T., W.-C.C., C.-C.L., and Y.-W.H. performed the experiments. P.O. designed and developed the FF mice. I.-C.H. conceived and designed the study, analyzed the data, and co-wrote the manuscript.

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Correspondence to Ya-Ting Chuang or I-Cheng Ho.

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The authors declare no competing interests.

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Tai, TS., Tsao, HW., Chuang, WC. et al. Ets1 regulates the differentiation and function of iNKT cells through both Pointed domain-dependent and domain-independent mechanisms. Cell Mol Immunol 17, 1198–1200 (2020). https://doi.org/10.1038/s41423-020-0382-2

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