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LILRB4 ITIMs mediate the T cell suppression and infiltration of acute myeloid leukemia cells

A Correction to this article was published on 31 January 2020

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Abstract

We recently demonstrated that leukocyte Ig-like receptor 4 (LILRB4) expressed by monocytic acute myeloid leukemia (AML) cells mediates T-cell inhibition and leukemia cell infiltration via its intracellular domain. The cytoplasmic domain of LILRB4 contains three immunoreceptor tyrosine-based inhibitory motifs (ITIMs); the tyrosines at positions 360, 412, and 442 are phosphorylation sites. Here, we analyzed how the ITIMs of LILRB4 in AML cells mediate its function. Our in vitro and in vivo data show that Y412 and Y442, but not Y360, of LILRB4 are required for T-cell inhibition, and all three ITIMs are needed for leukemia cell infiltration. We constructed chimeric proteins containing the extracellular domain of LILRB4 and the intracellular domain of LILRB1 and vice versa. The intracellular domain of LILRB4, but not that of LILRB1, mediates T-cell suppression and AML cell migration. Our studies thus defined the unique signaling roles of LILRB4 ITIMs in AML cells.

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  • 31 January 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Acknowledgements

We thank the National Cancer Institute (1R01CA172268), the Cancer Prevention and Research Institute of Texas (RP180435), the Robert A. Welch Foundation (I-1834), China Natural Science Foundation (81872332), Shandong Natural Science Foundation (2018GSF118201), and Yantai Science and Technology Development Plan (2018ZHGY070) for generous support.

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Contributions

ZL.L., M.D., and CC.Z. designed the study and wrote the paper. ZL.L., M.D., FF.H., HY.C., XY.L., and LC.H. performed the mouse experiments. ZL.L., FF.H., CZ.J., and S.S. performed the flow cytometry analysis and western blotting. ZL.L., M.D., HY.C., XY.L., and AH.S. performed the CRISPR-Cas9 experiments and plasmid constructions. ZL.L. and M.D. performed the T-cell coculture and IHC. ZL.L., and M.D. performed the statistical analysis.

Corresponding author

Correspondence to Cheng Cheng Zhang.

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Competing interests

C.C.Z. is a scientific founder of Immune-Onc Therapeutics. C.C.Z. and M.D. hold equity in and have multiple patents licensed to Immune-Onc Therapeutics. The other authors declare no competing interests.

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Li, Z., Deng, M., Huang, F. et al. LILRB4 ITIMs mediate the T cell suppression and infiltration of acute myeloid leukemia cells. Cell Mol Immunol 17, 272–282 (2020). https://doi.org/10.1038/s41423-019-0321-2

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