Zhiwei You

All Publications

• Cholinergic regulation of thymocyte negative selection. Nature immunology Liu, S., Zheng, C., Nechanitzky, R., Luo, P., Ramachandran, P., Nguyen, D., Elia, A. J., Moghadas Jafari, S., Law, R., Snow, B. E., Wakeham, A. C., Berger, T., Chen, H., Gill, K. T., Mcwilliam, R., Fortin, J., Modares, N. F., Saunders, M. E., Murakami, K., Qiu, Y., You, Z., Mohtashami, M., Qi, H., Ohashi, P. S., Zúñiga-Pflücker, J. C., Mak, T. W. 2025; 26 (6): 881-893

  Abstract

  The immune and nervous systems use a common chemical language for communication, namely, the cholinergic signaling involving acetylcholine (ACh) and its receptors (AChRs). Whether and how this language also regulates the development of the immune system is poorly understood. Here, we show that mouse CD4+CD8+ double-positive thymocytes express high levels of α9 nicotinic AChR (nAChR) and that this receptor controls thymic negative selection. α9 nAChR-deficient mice show an altered T cell receptor (TCR) repertoire and reduced CD4+ and CD8+ T cells in a mixed bone marrow chimera setting. α9 nAChR-mediated signaling regulates TCR strength and thymocyte survival. Thymic tuft cells, B cells and some T cells express choline acetyltransferase and are potential ACh sources, with ACh derived from T cells having the most important role. Furthermore, α9 nAChR deficiency during thymocyte development contributes to the altered development of autoimmune diseases in mice. Our results thus reveal a mechanism controlling immune cell development that involves cholinergic signaling.

  View details for DOI 10.1038/s41590-025-02152-4

  View details for PubMedID 40399609

  View details for PubMedCentralID 3466476

• A common thalamic hub for general and defensive arousal control. Neuron Wang, Y., You, L., Tan, K., Li, M., Zou, J., Zhao, Z., Hu, W., Li, T., Xie, F., Li, C., Yuan, R., Ding, K., Cao, L., Xin, F., Shang, C., Liu, M., Gao, Y., Wei, L., You, Z., Gao, X., Xiong, W., Cao, P., Luo, M., Chen, F., Li, K., Wu, J., Hong, B., Yuan, K. 2023; 111 (20): 3270-3287.e8

  Abstract

  The expression of defensive responses to alerting sensory cues requires both general arousal and a specific arousal state associated with defensive emotions. However, it remains unclear whether these two forms of arousal can be regulated by common brain regions. We discovered that the medial sector of the auditory thalamus (ATm) in mice is a thalamic hub controlling both general and defensive arousal. The spontaneous activity of VGluT2-expressing ATm (ATmVGluT2+) neurons was correlated with and causally contributed to wakefulness. In sleeping mice, sustained ATmVGluT2+ population responses were predictive of sensory-induced arousal, the likelihood of which was markedly decreased by inhibiting ATmVGluT2+ neurons or multiple downstream pathways. In awake mice, ATmVGluT2+ activation led to heightened arousal accompanied by excessive anxiety and avoidance behavior. Notably, blocking their neurotransmission abolished alerting stimuli-induced defensive behaviors. These findings may shed light on the comorbidity of sleep disturbances and abnormal sensory sensitivity in specific brain disorders.

  View details for DOI 10.1016/j.neuron.2023.07.007

  View details for PubMedID 37557180

• Neuronal regulation of B-cell immunity: Anticipatory immune posturing? Neuron You, Z., Liu, B., Qi, H. 2022; 110 (21): 3582-3596

  Abstract

  The brain may sense, evaluate, modulate, and intervene in the operation of immune system, which would otherwise function autonomously in defense against pathogens. Antibody-mediated immunity is one arm of adaptive immunity that may achieve sterilizing protection against infection. Lymphoid organs are densely innervated. Immune cells supporting the antigen-specific antibody response express receptors for neurotransmitters and glucocorticoid hormones, and they are subjected to collective regulation by the neuroendocrine and the autonomic nervous system. Emerging evidence reveals a brain-spleen axis that regulates antigen-specific B cell responses and antibody-mediated immunity. In this article, we provide a synthesis of those studies as pertinent to neuronal regulation of B cell responses in secondary lymphoid organs. We propose the concept of defensive immune posturing as a brain-initiated top-down reaction in anticipation of potential tissue injury that requires immune protection.

  View details for DOI 10.1016/j.neuron.2022.10.014

  View details for PubMedID 36327899

• Particulate-Based Single-Dose Local Immunosuppressive Regimen for Inducing Tolerogenic Dendritic Cells in Xenogeneic Islet Transplantation. Advanced healthcare materials Pathak, S., Acharya, S., Regmi, S., Shrestha, P., You, Z., Bae, Y. K., Park, M. H., Yook, S., Kim, J., Park, S. Y., Jeong, D., Yong, C. S., Kim, J. O., Chang, J. H., Jeong, J. 2020: e2001157

  Abstract

  Recent studies emphasize on developing immune tolerance by an interim administration of various immunosuppressive drugs. In this study, a robust protocol is reported for local immunomodulation using a single-dose of FK506 microspheres and clodronate liposomes (mFK+CLO) in a xenogeneic model of islet transplantation. Surprisingly, the single-dose treatment with mFK+CLO induce tolerance to the islet xenograft. The recipient mice display tolerogenic dendritic cells (tDCs) with decreased antigen presenting ability and T cell activation capacity. Furthermore, a reduced percentage of CD4+ and CD8+ T cells and an impaired differentiation of naive CD4+ T cells into interferon-gamma producing Th1 and interleukin-17 producing Th17 cells are observed. In addition, the immunosuppressive protocol leads to the generation of Foxp3+ regulatory T cells (Tregs) which are required for the long-term graft survival. The enhanced generation of tDCs and Tregs by the single treatment of mFK+CLO cause xenograft tolerance, suggesting a possible clinical strategy which may pave the way towards improving therapeutic outcomes of clinical islet transplantation.

  View details for DOI 10.1002/adhm.202001157

  View details for PubMedID 33251762

• A common signaling pathway leading to degranulation in mast cells and its regulation by CCR1-ligand. Allergy Chang, H. W., Kanegasaki, S., Jin, F., Deng, Y., You, Z., Chang, J. H., Kim, D. Y., Timilshina, M., Kim, J. R., Lee, Y. J., Toyama-Sorimachi, N., Tsuchiya, T. 2020; 75 (6): 1371-1381

  Abstract

  Signal transduction pathways mediated by various receptors expressed on mast cells are thought to be complex, and inhibitory signals that turn off activating signals are not known.Upstream signaling cascades mediated by several known receptors in bone marrow-derived mast cells that lead to degranulation and mediator release were studied by immunoblotting and immunoprecipitation. Small interfering RNAs and knockout mice were used to confirm findings.All ligands tested including IgE/Ag, SCF, HSP70, CCL3, and its valiant eMIP induced phosphorylation of linker for activation of T cells (LAT), which triggered their receptor-mediated downstream signaling cascades that controlled degranulation and mediator release. Phosphorylation of lymphocyte-specific protein kinase (Lck) was induced by each ligand, which commonly played an indispensable role in LAT phosphorylation. In contrast, phosphorylation of spleen tyrosine kinase was additionally induced in cells stimulated only with IgE/Ag and SCF, which is also associated with LAT phosphorylation in part. Degranulation and mediator release induced by IgE/Ag, SCF, or HSP70 were enhanced by nanomolar doses of CCR1 ligands CCL3 and eMIP via enhanced LAT phosphorylation. On the other hand, micromolar doses of CCR1 ligand inhibited degranulation and mediator release from mast cells stimulated with IgE/Ag, SCF, or HSP70 by de-phosphorylation of phosphorylated Lck with Src homology region 2 domain-containing phosphatase-1.Linker for activation of T cells plays a central role in signal transduction pathways in mast cells stimulated with any ligand tested. Dose-dependent alternate costimulation and inhibition of CCR1 ligands in IgE/Ag-, SCF-, or HSP70-stimulated mast cells occur at the level of Lck-LAT phosphorylation.

  View details for DOI 10.1111/all.14186

  View details for PubMedID 31954080

• Engineering "cell-particle hybrids" of pancreatic islets and bioadhesive FK506-loaded polymeric microspheres for local immunomodulation in xenogeneic islet transplantation. Biomaterials Nguyen, T. T., Pham, T. T., Nguyen, H. T., Nepal, M. R., Phung, C. D., You, Z., Katila, N., Pun, N. T., Jeong, T. C., Choi, D. Y., Park, P. H., Yong, C. S., Kim, J. O., Yook, S., Jeong, J. H. 2019; 221: 119415

  Abstract

  Host immune response remains an obstacle in cell-replacement therapy for treating type I diabetes. Long-term systemic immunosuppression results in suboptimal efficacy and adverse reactions. Thus, "cell-particle hybrids" of pancreatic islets and tissue-adhesive, polydopamine-coated, FK506-loaded biodegradable microspheres (PD-FK506-MS) were developed to locally modulate the immune response at the transplantation site. Coating of FK506-MS with PD enabled the rapid formation of stable cell-particle hybrids without significant changes in islet viability and functionality. Extremely low quantities of FK506 (approximately 600 ng per recipient) sustainably released from cell-particle hybrids effectively prolonged survival of xenogeneic islet graft. Interestingly, FK506 exhibited extended bioavailability in the grafts but was undetectable in systemic circulation and other tissues. Moreover, mRNA expression of inflammatory cytokines was significantly inhibited in the PD-FK506-MS-containing grafts but not in lymphoid organs. This study presents a promising platform that facilitates the translation of local immunomodulation towards an effective strategy with improved safety profiles for treating type I diabetes.

  View details for DOI 10.1016/j.biomaterials.2019.119415

  View details for PubMedID 31419652

• Activation of Mevalonate Pathway via LKB1 Is Essential for Stability of T-reg Cells CELL REPORTS Timilshina, M., You, Z., Lacher, S. M., Acharya, S., Jiang, L., Kang, Y., Kim, J., Chang, H., Kim, K., Park, B., Song, J., Ko, H., Park, Y., Ma, M., Nepal, M., Jeong, T., Chung, Y., Waisman, A., Chang, J. 2019; 27 (10): 2948-+

  Abstract

  The function of regulatory T (Treg) cells depends on lipid oxidation. However, the molecular mechanism by which Treg cells maintain lipid metabolism after activation remains elusive. Liver kinase B1 (LKB1) acts as a coordinator by linking cellular metabolism to substrate AMP-activated protein kinase (AMPK). We show that deletion of LKB1 in Treg cells exhibited reduced suppressive activity and developed fatal autoimmune inflammation. Mechanistically, LKB1 induced activation of the mevalonate pathway by upregulating mevalonate genes, which was essential for Treg cell functional competency and stability by inducing Treg cell proliferation and suppressing interferon-gamma and interleukin-17A expression independently of AMPK. Furthermore, LKB1 was found to regulate intracellular cholesterol homeostasis and to promote the mevalonate pathway. In agreement, mevalonate and its metabolite geranylgeranyl pyrophosphate inhibited conversion of Treg cells and enhanced survival of LKB1-deficient Treg mice. Thus, LKB1 is a key regulator of lipid metabolism in Treg cells, involved in optimal programming of suppressive activity, immune homeostasis, and tolerance.

  View details for DOI 10.1016/j.celrep.2019.05.020

  View details for Web of Science ID 000470098200014

  View details for PubMedID 31167140

• BJ-2266 ameliorates experimental autoimmune encephalomyelitis through down-regulation of the JAK/STAT signaling pathway. European journal of immunology You, Z., Timilshina, M., Jeong, B. S., Chang, J. H. 2017; 47 (9): 1488-1500

  Abstract

  CD4+ T cells differentiate into distinct effector subsets upon antigenic stimulation. Cytokines, and micro-environmental factors present during T-cell priming, direct differentiation of naïve CD4+ T cells into pro-inflammatory Th1 and Th17 cells. From extensive screening of 2,4,5-trimethylpyridin-3-ol derivatives with various functional groups at C(6)-position, BJ-2266, a 6-thioureido-derivative, showed potent inhibitory activity on in vitro T helper (Th)-cell differentiation. This compound inhibited IFN-γ and IL-17 production from polyclonal CD4+ T cells and ovalbumin (OVA)-specific CD4+ T cells that were activated by T-cell receptor (TCR) engagement. We assessed the inhibitory effect of BJ-2266 in experimental autoimmune encephalomyelitis (EAE). Our results suggest that BJ-2266 treatment significantly suppresses EAE disease progression with reduced generation of Th1 and Th17 cells. Notably, Th-cell differentiation was significantly suppressed by BJ-2266 treatment with no effect on apoptosis, activation and proliferation of activated T cells. Furthermore, adoptive transfer of BJ-2266 treated MOG-reactive Th1 and Th17 cells led to a lower EAE disease score and better clinical recovery from EAE. The underlying mechanism of BJ-2266 effect involved the inhibition of JAK/STAT phosphorylation that is critical for Th-cell differentiation. We conclude that BJ-2266 regulates the JAK/STAT pathway in response to cytokine signals and subsequently suppresses the differentiation of Th-cell responses.

  View details for DOI 10.1002/eji.201646860

  View details for PubMedID 28681958

• BJ-3105, a 6-Alkoxypyridin-3-ol Analog, Impairs T Cell Differentiation and Prevents Experimental Autoimmune Encephalomyelitis Disease Progression. PloS one Timilshina, M., Kang, Y., Dahal, I., You, Z., Nam, T. G., Kim, K. J., Jeong, B. S., Chang, J. H. 2017; 12 (1): e0168942

  Abstract

  CD4+ T cells are essential in inflammation and autoimmune diseases. Interferon-γ (IFN-γ) secreting T helper (Th1) and IL-17 secreting T helper (Th17) cells are critical for several autoimmune diseases. To assess the inhibitory effect of a given compound on autoimmune disease, we screened many compounds with an in vitro Th differentiation assay. BJ-3105, a 6-alkoxypyridin-3-ol analog, inhibited IFN-γ and IL-17 production from polyclonal CD4+ T cells and ovalbumin (OVA)-specific CD4+ T cells which were activated by T cell receptor (TCR) engagement. BJ-3105 ameliorated the experimental autoimmune encephalomyelitis (EAE) model by reducing Th1 and Th17 generation. Notably, Th cell differentiation was significantly suppressed by BJ-3105 treatment without inhibiting in vitro proliferation of T cells or inducing programmed cell death. Mechanistically, BJ-3105 inhibited the phosphorylation of JAK and its downstream signal transducer and activator of transcription (STAT) that is critical for Th differentiation. These results demonstrated that BJ-3105 inhibits the phosphorylation of STAT in response to cytokine signals and subsequently suppressed the differentiation of Th cell responses.

  View details for DOI 10.1371/journal.pone.0168942

  View details for PubMedID 28095433

  View details for PubMedCentralID PMC5241145