Honghui Liu

All Publications

• Facile induction of immune tolerance by an interleukin-2-TGFβ surrogate agonist. Nature Sun, Q., Barrett, A. K., Ogishi, M., Lyu, H., Jiang, H., Liu, H., Zhao, Y., Rodriguez, G. E., Tao, P., Obenaus, M., Householder, K. D., Tang, Q., Lanz, T. V., Garcia, K. C. 2026

  Abstract

  CD4+ regulatory T cells (Treg cells) are essential for immune tolerance1. Peripherally induced Treg cells (pTreg cells) complement thymic Treg cells by broadening Treg cell reactivity in response to a changing antigenic landscape2. Although both TGFβ and IL-2 synergistically promote functional pTreg cell development in vitro3-6, their combined roles in inducing pTreg cell generation in vivo have not been exploited for tolerizing immunotherapy. Here we designed an IL-2-TGFβ 'surrogate' co-agonist by creating a single-chain fusion protein between IL-2 and a low-affinity TGFβ mimic agonist derived from a helminth parasite7. This IL-2-TGFβ surrogate functions as an AND-gated co-agonist and enabled simultaneous cis-activation of IL-2-STAT5 and TGFβ-SMAD2/3 signalling specifically in T cells that express IL-2 receptors. The IL-2-TGFβ surrogate agonist robustly induced antigen-specific, functional and stable pTreg cells in vivo within peripheral lymphoid organs in mice immunized with ovalbumin (OVA) and myelin oligodendrocyte glycoprotein (MOG)35-55. The induced pTreg cells display an effector-like, actively expanding state with high RORγt expression, enabling efficient migration and suppression of intestinal inflammation. Treatment with this agonist effectively quelled immune activation in mouse models of allergen-induced allergic inflammation and self-antigen-driven autoimmune neuroinflammation, suggesting a strategy for the induction of antigen-specific pTreg cells in vivo to establish immune tolerance in inflammatory, allergic and autoimmune diseases.

  View details for DOI 10.1038/s41586-026-10208-0

  View details for PubMedID 41813890

  View details for PubMedCentralID 2194145

• Enhanced potency of an IgM-like nanobody targeting conserved epitope in SARS-CoV-2 spike N-terminal domain. Signal transduction and targeted therapy Liu, B., Liu, H., Han, P., Wang, X., Wang, C., Yan, X., Lei, W., Xu, K., Zhou, J., Qi, J., Fan, R., Wu, G., Tian, W. X., Gao, G. F., Wang, Q. 2024; 9 (1): 131

  Abstract

  Almost all the neutralizing antibodies targeting the receptor-binding domain (RBD) of spike (S) protein show weakened or lost efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged or emerging variants, such as Omicron and its sub-variants. This suggests that highly conserved epitopes are crucial for the development of neutralizing antibodies. Here, we present one nanobody, N235, displaying broad neutralization against the SARS-CoV-2 prototype and multiple variants, including the newly emerged Omicron and its sub-variants. Cryo-electron microscopy demonstrates N235 binds a novel, conserved, cryptic epitope in the N-terminal domain (NTD) of the S protein, which interferes with the RBD in the neighboring S protein. The neutralization mechanism interpreted via flow cytometry and Western blot shows that N235 appears to induce the S1 subunit shedding from the trimeric S complex. Furthermore, a nano-IgM construct (MN235), engineered by fusing N235 with the human IgM Fc region, displays prevention via inducing S1 shedding and cross-linking virus particles. Compared to N235, MN235 exhibits varied enhancement in neutralization against pseudotyped and authentic viruses in vitro. The intranasal administration of MN235 in low doses can effectively prevent the infection of Omicron sub-variant BA.1 and XBB in vivo, suggesting that it can be developed as a promising prophylactic antibody to cope with the ongoing and future infection.

  View details for DOI 10.1038/s41392-024-01847-8

  View details for PubMedID 38740785

  View details for PubMedCentralID PMC11091055

• Two pan-SARS-CoV-2 nanobodies and their multivalent derivatives effectively prevent Omicron infections in mice. Cell reports. Medicine Liu, H., Wu, L., Liu, B., Xu, K., Lei, W., Deng, J., Rong, X., Du, P., Wang, L., Wang, D., Zhang, X., Su, C., Bi, Y., Chen, H., Liu, W. J., Qi, J., Cui, Q., Qi, S., Fan, R., Jiang, J., Wu, G., Gao, G. F., Wang, Q. 2023; 4 (2): 100918

  Abstract

  With the widespread vaccinations against coronavirus disease 2019 (COVID-19), we are witnessing gradually waning neutralizing antibodies and increasing cases of breakthrough infections, necessitating the development of drugs aside from vaccines, particularly ones that can be administered outside of hospitals. Here, we present two cross-reactive nanobodies (R14 and S43) and their multivalent derivatives, including decameric ones (fused to the immunoglobulin M [IgM] Fc) that maintain potent neutralizing activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) after aerosolization and display not only pan-SARS-CoV-2 but also varied pan-sarbecovirus activities. Through respiratory administration to mice, monovalent and decameric R14 significantly reduce the lung viral RNAs at low dose and display potent pre- and post-exposure protection. Furthermore, structural studies reveal the neutralizing mechanisms of R14 and S43 and the multiple inhibition effects that the multivalent derivatives exert. Our work demonstrates promising convenient drug candidates via respiratory administration against SARS-CoV-2 infection, which can contribute to containing the COVID-19 pandemic.

  View details for DOI 10.1016/j.xcrm.2023.100918

  View details for PubMedID 36702124

  View details for PubMedCentralID PMC9834170