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New insights into the role of the immune inhibitory receptor VSTM1 in autoimmune disease

Cellular & Molecular Immunology volume 21, pages 95–96 (2024)Cite this article

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Immune inhibitory receptors (IRs) are germline-encoded transmembrane receptors that function as negative regulators of immune cells and dampen the cellular response to keep the immune system in balance [1]. There are more than 300 potential immune IRs encoded in the human genome [2]. The most studied IRs in cancer immunity are programmed cell death protein 1, cytotoxic T lymphocyte protein 4 in T cells, and killer cell Ig-like IRs on NK cells [3]. In autoimmunity, recent studies have detailed the crucial impact of IRs, which mediate peripheral tolerance and immune signaling inhibition. Deletion or blockade in mice and IR disruption in humans both positively correlated with disease outcomes, e.g., LAG3, TIM3 and TIGIT [4]. However, how IRs are sensed by different ligands, and thus alter the immune inhibitor response in autoimmune diseases, is unknown.

Upon ligation, signaling from immune IRs is transduced through immunoreceptor tyrosine-based inhibitory motifs (ITIMs) oriented in the cytoplasmic tail of the receptor [5]. One member of the IR family is V-set and transmembrane domain-containing 1 (VSTM1), the gene encoding signal inhibitory receptor on leukocytes-1 [6]. VSTM1 consists of extracellular, transmembrane and intracellular sequences. Once phosphorylated, VSTM1 acts as a docking site for the recruitment of the Src homology 2 domain-containing tyrosine phosphatases SHP1 and SHP2 [7]. The primary VSTM1-expressing cells are human myeloid cells, which restrict essential activation of the immune response, such as Fc receptor-induced ROS production and increased respiration [8]. Although signaling downstream of VSTM1 by Src family kinases has been well studied, the natural ligand of VSTM1 is not yet known. In the latest issue of Cellular and Molecular Immunology, Xu Jiang et al. reported that oxidized galectin-1 (Gal-1) in SLE does not bind the IR VSTM1 and increases reactive oxygen species (ROS) levels in neutrophils [9].

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Acknowledgements

This work is supported by the National Natural Science Foundation of China (82371760) to JW.

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  1. Center for Immune-related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Naijun Miao & Jing Wang

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  1. Naijun Miao
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NJM drafted the manuscript and drew the figure. JW revised and finalized the manuscript.

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Correspondence to Jing Wang.

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Miao, N., Wang, J. New insights into the role of the immune inhibitory receptor VSTM1 in autoimmune disease. Cell Mol Immunol 21, 95–96 (2024). https://doi.org/10.1038/s41423-023-01097-8

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