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Paper Readig Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy  Jun Wang, Jingwei Sun, Linda N. Liu, Dallas B. Flies, Xinxin Nie, Maria Toki, Jianping Zhang, Chang Song, Melissa Zarr, Xu Zhou, Xue Han, Kristina A. Archer, Thomas O’Neill, Roy S. Herbst, Agedi N. Boto, Miguel F. Sanmamed, Solomon Langermann, David L. Rimm and Lieping Chen. NATURE MEDICINE (2019) Jun Wang’s team built a genome-scale T cell activity array (TCAA) to identify cell surface molecules that regulate T cell activity in vitro. By the TCAA system, the team found that Siglec-15 consistently inhibited T cell activity and was therefore selected for follow-up studies. Siglec-15 is a sialyl-binding immunoglobulin-like lectin family gene that encodes a very short extracellular domain. The data suggest that Siglec-15 is closely related to the B7 gene family, possibly share immune regulation ability with B7 family members. The team then found that Siglec-15 mRNA is rarely expressed in most normal human tissues and various immune cell subpopulations, but can be found in macrophages. Using Siglec-15 systemic knockout mice and conditional Siglec-15 knockout in macrophages of mouse model, the researchers found that the Siglec-15 gene knockout did not cause autoimmune disease or other symptoms in mice, demonstrating that macrophage/myeloid-derived Siglec-15 could inhibit the immune response of antigen-specific T cells by regulating cell growth. Then, through the meta-analysis of the TCGA database, the team found that Siglec-15 mRNA expression was up-regulated in a variety of human tumors. There was no correlation between B7-H1 (PD-L1) and Siglec-15 expression, and only 7/218 (3.2%) cases were positive for both markers. Finally, the researchers used mouse tumor models to further demonstrate that Siglec-15 is a potential candidate for tumor immunotherapy normalization strategies. In addition, the team designed the anti-Siglec-15 monoclonal antibody α-S15, which was used in a variety of mouse tumor models and found to block the immunosuppressive effects of macrophage/myeloid cell-derived Siglec-15. https:///10.1038/s41591-019-0374-x Beyond Type 1 Regulatory T Cells: Co-expression of LAG3 and CD49b in IL-10-Producing T Cell Lineages.  Weishan Huang, Sabrina Solouki, Chavez Carter, Song-Guo Zheng and Avery August. Frontiers in Immunology(2019) IL-10 is expressed by many cell subsets of the adaptive immune system, including B cells and T cells comprising the Foxp3− CD4+, Foxp3+ Treg and CD8+ T cell subsets. Among the IL-10-producing T cells, the Foxp3- CD4+ T cell subset, also known as type 1 regulatory T cells (Tr1 cells), have been shown to prevent allergic asthma and atopic dermatitis in murine models. co-expression of LAG3 and CD49b has been recently proposed to be a cell surface signature of the Foxp3- IL-10high Tr1 cells. Given the importance of being able to identify Foxp3- Tr1 cells, they sought to determine whether co-expression of LAG3 and CD49b can mark a broader range of T cell subsets that are actively producing high levels of IL-10. Using a murine model carrying an IL-10GFP/Foxp3RFP dual reporter system, they find that co-expression of LAG3 and CD49b is a generic feature of the IL-10-producing Foxp3- CD4+, Foxp3+ CD4+, and CD8+ T cell subsets. The capacity of co-expression of LAG3 and CD49b in marking IL-10high T cell subsets is dependent on the disease conditions and anatomical location of the cells. Furthermore, co-expression of LAG3 and CD49b is also a shared feature of human IL-10-producing FOXP3- CD4+, FOXP3+ CD4+, and CD8+ T cell subsets. These data reveal that co-expression of LAG3 and CD49b is a generic signature of IL-10-producing T cells, which is broader than previously appreciated. Edited by Biaolong Deng |
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