All Publications

  • KIR+CD8+ T cells suppress pathogenic T cells and are active in autoimmune diseases and COVID-19. Science (New York, N.Y.) Li, J., Zaslavsky, M., Su, Y., Guo, J., Sikora, M. J., van Unen, V., Christophersen, A., Chiou, S., Chen, L., Li, J., Ji, X., Wilhelmy, J., McSween, A. M., Palanski, B. A., Mallajosyula, V. V., Bracey, N. A., Dhondalay, G. K., Bhamidipati, K., Pai, J., Kipp, L. B., Dunn, J. E., Hauser, S. L., Oksenberg, J. R., Satpathy, A. T., Robinson, W. H., Dekker, C. L., Steinmetz, L. M., Khosla, C., Utz, P. J., Sollid, L. M., Chien, Y., Heath, J. R., Fernandez-Becker, N. Q., Nadeau, K. C., Saligrama, N., Davis, M. M. 2022: eabi9591


    Here we find that CD8+ T cells expressing inhibitory killer cell immunoglobulin-like receptors (KIRs) are the human equivalent of Ly49+CD8+ regulatory T cells in mice and are increased in the blood and inflamed tissues of patients with a variety of autoimmune diseases. Moreover, these CD8+ T cells efficiently eliminated pathogenic gliadin-specific CD4+ T cells from celiac disease patients' leukocytes in vitro. We also find elevated levels of KIR+CD8+ T cells, but not CD4+ regulatory T cells, in COVID-19 patients, which correlated with disease severity and vasculitis. Selective ablation of Ly49+CD8+ T cells in virus-infected mice led to autoimmunity post infection. Our results indicate that in both species, these regulatory CD8+ T cells act uniquely to suppress pathogenic T cells in autoimmune and infectious diseases.

    View details for DOI 10.1126/science.abi9591

    View details for PubMedID 35258337

  • Nanoparticle-enabled innate immune stimulation activates endogenous tumor-infiltrating T cells with broad antigen specificities PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Yin, Q., Yu, W., Grzeskowiak, C. L., Li, J., Huang, H., Guo, J., Chen, L., Wang, F., Zhao, F., von Boehmer, L., Metzner, T. J., Leppert, J. T., Chien, Y., Kuo, C. J., Davis, M. M. 2021; 118 (21)
  • Nanoparticle-enabled innate immune stimulation activates endogenous tumor-infiltrating T cells with broad antigen specificities. Proceedings of the National Academy of Sciences of the United States of America Yin, Q., Yu, W., Grzeskowiak, C. L., Li, J., Huang, H., Guo, J., Chen, L., Wang, F., Zhao, F., von Boehmer, L., Metzner, T. J., Leppert, J. T., Chien, Y., Kuo, C. J., Davis, M. M. 2021; 118 (21)


    Tumors are often infiltrated by T lymphocytes recognizing either self- or mutated antigens but are generally inactive, although they often show signs of prior clonal expansion. Hypothesizing that this may be due to peripheral tolerance, we formulated nanoparticles containing innate immune stimulants that we found were sufficient to activate self-specific CD8+ T cells and injected them into two different mouse tumor models, B16F10 and MC38. These nanoparticles robustly activated and/or expanded antigen-specific CD8+ tumor-infiltrating T cells, along with a decrease in regulatory CD4+ T cells and an increase in Interleukin-17 producers, resulting in significant tumor growth retardation or elimination and the establishment of immune memory in surviving mice. Furthermore, nanoparticles with modification of stimulating human T cells enabled the robust activation of endogenous T cells in patient-derived tumor organoids. These results indicate that breaking peripheral tolerance without regard to the antigen specificity creates a promising pathway for cancer immunotherapy.

    View details for DOI 10.1073/pnas.2016168118

    View details for PubMedID 34021082

  • Antitumor effects of iPSC-based cancer vaccine in pancreatic cancer. Stem cell reports Ouyang, X., Liu, Y., Zhou, Y., Guo, J., Wei, T., Liu, C., Lee, B., Chen, B., Zhang, A., Casey, K. M., Wang, L., Kooreman, N. G., Habtezion, A., Engleman, E. G., Wu, J. C. 2021


    Induced pluripotent stem cells (iPSCs) and cancer cells share cellular similarities and transcriptomic profiles. Here, we show that an iPSC-based cancer vaccine, comprised of autologous iPSCs and CpG, stimulated cytotoxic antitumor CD8+ Tcell effector and memory responses, induced cancer-specific humoral immune responses, reduced immunosuppressive CD4+ T regulatory cells, and prevented tumor formation in 75% of pancreatic ductal adenocarcinoma (PDAC) mice. We demonstrate that shared gene expression profiles of "iPSC-cancer signature genes" and others are overexpressed in mouse and human iPSC lines, PDAC cells, and multiple human solid tumor types compared with normal tissues. These results support further studies of iPSC vaccination in PDAC in preclinical and clinical models and in other cancer types that have low mutational burdens.

    View details for DOI 10.1016/j.stemcr.2021.04.004

    View details for PubMedID 33961792

  • Bifidobacterium alters the gut microbiota and modulates the functional metabolism of T regulatory cells in the context of immune checkpoint blockade. Proceedings of the National Academy of Sciences of the United States of America Sun, S., Luo, L., Liang, W., Yin, Q., Guo, J., Rush, A. M., Lv, Z., Liang, Q., Fischbach, M. A., Sonnenburg, J. L., Dodd, D., Davis, M. M., Wang, F. 2020


    Immune checkpoint-blocking antibodies that attenuate immune tolerance have been used to effectively treat cancer, but they can also trigger severe immune-related adverse events. Previously, we found that Bifidobacterium could mitigate intestinal immunopathology in the context of CTLA-4 blockade in mice. Here we examined the mechanism underlying this process. We found that Bifidobacterium altered the composition of the gut microbiota systematically in a regulatory T cell (Treg)-dependent manner. Moreover, this altered commensal community enhanced both the mitochondrial fitness and the IL-10-mediated suppressive functions of intestinal Tregs, contributing to the amelioration of colitis during immune checkpoint blockade.

    View details for DOI 10.1073/pnas.1921223117

    View details for PubMedID 33077598

  • MCPIP1 inhibits Hepatitis B virus replication by destabilizing viral RNA and negatively regulates the virus-induced innate inflammatory responses. Antiviral research Li, M. n., Yang, J. n., Zhao, Y. n., Song, Y. n., Yin, S. n., Guo, J. n., Zhang, H. n., Wang, K. n., Wei, L. n., Li, S. n., Xu, W. n. 2020; 174: 104705


    Monocyte chemotactic protein-induced protein 1 (MCPIP1) is an inflammatory regulator in immune response. Recently, MCPIP1 has also been identified as a host antiviral factor against certain virus infection including human immunodeficiency virus, dengue virus and hepatitis C virus. However, whether MCPIP1 could restrict the replication of hepatitis B virus (HBV), a DNA pararetrovirus belonging to Hepadnaviridae family, has not been investigated. In this study, we found that MCPIP1 expression was up-regulated in mouse livers upon acute HBV replication and in HBV-replicated hepatoma cells or HBV-stimulated macrophages. Enforced MCPIP1 expression by hydrodynamic DNA injection in vivo significantly inhibited HBV replication in the mouse livers. Then in vitro studies by overexpression or knockdown assays in cell-lines identified the direct antiviral effect of MCPIP1 on HBV replication. RNA immunoprecipitation and decay assay further suggested that MCPIP1 potently restricted HBV replication through directly binding viral RNA and degrading RNA via its RNase activity, but not deubiquitinase activity. Moreover, we further verified that MCPIP1 negatively regulated HBV-induced proinflammatory cytokines, such as IL-1β, TNF-α and IL-6 in macrophages. Taken together, our data expand MCPIP1's range of viral targets to DNA virus and also demonstrate the negative regulatory role of MCPIP1 in suppressing virus-induced inflammatory response, suggesting MCPIP1 as a potential therapeutic target for treating HBV-related diseases via inducing a host defense against HBV and reducing inflammatory injury meanwhile.

    View details for DOI 10.1016/j.antiviral.2020.104705

    View details for PubMedID 31926181