1. CD8 cells in immune regulation and development of autoimmune diseases： CD8+ regulatory T cells play key roles in maintaining self-tolerance. We have been focused on the study of Qa1-restricted CD8+ regulatory cells in mice. We have discovered that the suppressive activity of these regulatory cells was tightly regulated by the interaction of CD94/NKG2A and Qa1. Disruption of the CD94/NKG2A-Qa1 by either site-directed mutagenesis or antibody blockade enables the maximum release of NK and CD8+ suppressive activity and amelioration of autoimmune diseases such as EAE in mice（Lu et al. Immunity 2007, PNAS 2008）。We have recently reported that Glatiramer acetate, a FDA proved anti-MS drug, was able to induce Qa1-resricted CD8+ regulatory cells in mice, which could be used for the treatment of autoimmune IBD（Yao Y et al. Eur. J. Immunol. 2013）. We are currently exploring the role of CD8 subpopulations in anti-tumor and anti-viral responses. We are also interested in the equivalent subpopulation of CD8 regulatory cells in human and its relevance to human autoimmune and infectious diseases.
2. Thymocyte development and immune cell signaling：Programmed gene expression is critical for T-lineage cell differentiation as well as cell activation upon stimulation. We’ve analyzed the gene expression profile during thymocyte development in the thymus and identified an important adaptor protein Tespa1 (Wang et al. Nature Immunology 2012). Further analysis revealed that this molecule associates with TCR signaling components PLC-g1 and Grb2, and contributes to the activation of the Ca2+/NFAT pathways upon TCR engagement. We are currently investigating the molecular mechanisms how Tespa1 regulates TCR signaling as well as the role of some other important signaling molecules in regulating this development process.
3. Integrative signaling in Regulation of TH17 cell differentiation: TH17 cells (interleukin-17-producing helper T cells) are present at the sites of tissue inflam­mation and associated with the induction of multiple autoimmune diseases. The differentiation of TH17 cells is instructed and critically regulated by various cytokines in the microenvironment, which drive intracellular signaling process and transcription profiles that determine the cell fate. In our study, we found that MINK1, a germinal center kinase (GCK) family kinase, plays as a negative regulator for TH17 cell differentiation. We are currently investigating the mechanisms of this regulation.
Paper published in 5 years：
Liang J, Lyu J, Zhao M, Li D, Zheng M, Fang Y, Zhao F, Lou J, Guo C, Wang L, Wang D, Liu W* and Lu L*. Tespa1 regulates T cell receptor-induced calcium signals by recruiting inositol 1,4,5-trisphosphate receptors. Nature Communications (online)
Geng J, Yu S, Zhao H, Sun X, Li X, Wang P, Xiong X, Hong L, Xie C, Gao J, Shi Y, Peng J, Johnson RL, Xiao N, Lu L, Han J, Zhou D, Chen L. The transcriptional coactivator TAZ regulates reciprocal differentiation of TH17 cells and Treg cells. Nat Immunol. 2017 May 15. doi: 10.1038/ni.3748. [Epub ahead of print] (Pubmed)
Fu G, Xu Q, Qiu Y, Jin X, Xu T, Dong S, Wang J, Ke Y, Hu H, Cao X, Wang D, Cantor H, Gao X and Lu L*. Suppression of Th17 cell differentiation by misshapen/NIK-related kinase MINK1. J Exp Med. 2017 May 1;214(5):1453-1469. (Pubmed)
J Exp Med Insights： MINK1： The missing link between ROS and its inhibition of Th17 cells. Martinez GJ. J Exp Med. 2017 May 1;214(5):1205-1206. (LINK)
Zhang Y, Xu Y, Liu S, Guo X, Cen D, Xu J, Li H, Li K, Zeng C, Lu L, Zhou Y, Shen H, Cheng H, Zhang X, Ke Y*. Scaffolding protein Gab1 regulates myeloid dendritic cell migration in allergic asthma. Cell Res. 2016 Nov;26(11):1226-1241. (Pubmed)
Guo C, Xie S, Chi Z, Zhang J, Liu Y, Zhang L, Zheng M, Zhang X, Xia D, Ke Y, Lu L, Wang D*. Bile Acids Control Inflammation and Metabolic Disorder through Inhibition of NLRP3 Inflammasome. Immunity. 2016 Oct 18;45(4):802-816. (Pubmed)
Yue M, Luo D, Yu S, Liu P, Zhou Q, Hu M, Liu Y, Wang S, Huang Q, Niu Y, Lu L*, Hu H*. Misshapen/ NIK-related Kinase (MINK1) is involved in platelet function, hemostasis and thrombus formation. Blood. 2016 Feb 18;127(7):927-37. (Pubmed)
Yue Y, Huang W, Liang J, Guo J, Ji J, Yao Y, Zheng M, Cai Z, Lu L*, Wang J*. IL4I1 Is a Novel Regulator of M2 Macrophage Polarization That Can Inhibit T Cell Activation via L-Tryptophan and Arginine Depletion and IL-10 Production. PLoS One. 2015 Nov 24; 10(11):e0142979. doi: 10.1371/ journal.pone.0142979. eCollection 2015. (Pubmed)
Chen C, Li HQ, Liu YJ, Guo ZF, Wu HJ, Li X, Lou HF, Zhu L, Wang D, Li XM, Yu L, Cao X, Lu L, Gao Z, Duan SM*. A novel size-based sorting mechanism of pinocytic luminal cargoes in microglia. J Neurosci. 2015 Feb 11;35(6):2674-88. (Pubmed)
Wang D*, Zheng M, Qiu Y, Guo C, Ji J, Lei L, Zhang X, Liang J, Lou J, Huang W, Dong B, Wu S, Wang J, Ke Y, Cao X, Zhou YT and Lu L*, Tespa1 negatively regulates FcεRI-mediated signaling and the mast cell-mediated allergic response. J Exp. Med. 2014 Dec 15;211(13):2635-49. (Pubmed)
Lu L* and Wang J*, One way to pathogenesis, many ways to homeostasis. Cellular & Molecular Immunology 2013 10:2-3. (Commentary) (Pubmed)
Yao Y, Han W, Liang J, Ji Jian, Wan J, Cantor H, Lu L*, Glatiramer acetate ameliorates inflammatory bowel disease in mice through the induction of Qa-1-restricted CD8+ regulatory cells. Eur. J. Immunol. 2013 Jan;43(1):125-36. (Pubmed)
Chen X, Yin Z, Chen JL, Shen WL, Liu HH, Tang QM, Fang Z, Lu LR, Ji J, Ouyang HW*. Force and scleraxis synergistically promote the commitment of human ES cells derived MSCs to tenocytes. Sci Rep. 2012;2:977. (Pubmed)
Wang X, Cui Y, Luo G, Wang Q, Hu J, He W, Yuan J, Zhou J, Wu Y, Sun X, Robson S, Li X, Tan J, Peng Y, Xue G，Lu L, Gao W, Wu J*. Activated mouse CD4+Foxp3− T cells facilitate melanoma metastasis via Qa-1-dependent suppression of NK-cell cytotoxicity. Cell Research. 2012 Dec; 22 (12): 1696-706. (Pubmed)
Wang D, Zheng M, Lei L, Ji J, Yao Y, Qiu Y, Ma L, Lou J, Ouyang C, Zhang X, He Y, Chi J, Wang L, Kuang Y, Wang J, Cao X and Lu L*, Tespa1 is involved in late thymocyte development through the regulation of TCR-mediated signaling. Nature Immunology 13: 560–568 (2012). (Pubmed)
Nature Immunology News and Views: Tespa1: another gatekeeper for positive selection. by Nicholas R J Gascoigne & Guo Fu Nature Immunology 13,530–532(2012). (LINK)
Faculty 1000 Article Recommendation: New Finding, Interesting Hypothesis. (LINK)
Weng C, Dong H, Cheng G, Zhai Y, Bai R, Hu H, Lu L and Xu Z*, miR-409-3p inhibits HT1080 cell proliferation, vascularization and metastasis by targeting angiogenin. Cancer Lett. 2012 323(2): 171-179. (Pubmed)
The main focus of our lab is to elucidate the molecular pathways and cellular interactions that mediate and regulate thymocyte development and T cell-mediated immune responses by using molecular biology and genetic approaches. We are especially interested in the identification and characterization of novel immune-related molecules, and the development and treatment of cancer and autoimmune diseases.