Bing Wang

All Publications

• Identification of unstable regulatory and autoreactive effector T cells that are expanded in patients with FOXP3 mutations. Science translational medicine Borna, Š., Lee, E., Nideffer, J., Ramachandran, A., Wang, B., Baker, J., Mavers, M., Lakshmanan, U., Narula, M., Garrett, A. K., Schulze, J., Olek, S., Marois, L., Gernez, Y., Bhatia, M., Chong, H. J., Walter, J., Kitcharoensakkul, M., Lang, A., Cooper, M. A., Bertaina, A., Roncarolo, M. G., Meffre, E., Bacchetta, R. 2023; 15 (727): eadg6822

  Abstract

  Studies of the monogenic autoimmune disease immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) have elucidated the essential function of the transcription factor FOXP3 and thymic-derived regulatory T cells (Tregs) in controlling peripheral tolerance. However, the presence and the source of autoreactive T cells in IPEX remain undetermined. Here, we investigated how FOXP3 deficiency affects the T cell receptor (TCR) repertoire and Treg stability in vivo and compared T cell abnormalities in patients with IPEX with those in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED). To study Tregs independently of their phenotype and to analyze T cell autoreactivity, we combined Treg-specific demethylation region analyses, single-cell multiomic profiling, and bulk TCR sequencing. We found that patients with IPEX, unlike patients with APECED, have expanded autoreactive T cells originating from both autoreactive effector T cells (Teffs) and Tregs. In addition, a fraction of the expanded Tregs from patients with IPEX lost their phenotypic and functional markers, including CD25 and FOXP3. Functional experiments with CRISPR-Cas9-mediated FOXP3 knockout Tregs and Tregs from patients with IPEX indicated that the patients' Tregs gain a TH2-skewed Teff-like function, which is consistent with immune dysregulation observed in these patients. Analyses of FOXP3 mutation-carrier mothers and a patient with IPEX after hematopoietic stem cell transplantation indicated that Tregs expressing nonmutated FOXP3 prevent the accumulation of autoreactive Teffs and unstable Tregs. These findings could be directly used for diagnostic and prognostic purposes and for monitoring the effects of immunomodulatory treatments.

  View details for DOI 10.1126/scitranslmed.adg6822

  View details for PubMedID 38117899

• Loss of Lkb1 in CD11c+ myeloid cells protects mice from diet-induced obesity while enhancing glucose intolerance and IL-17/IFN-γ imbalance. Cellular and molecular life sciences : CMLS Sun, Y., Wang, B., Hu, Q., Zhang, H., Lai, X., Wang, T., Zhao, C., Wang, J., Zhang, X., Niu, Q., He, B., Jiang, E., Shi, M., Feng, X., Luo, Y. 2023; 80 (3): 63

  Abstract

  Adipose tissue CD11c+ myeloid cell is an independent risk factor associated with obesity and metabolic disorders. However, the underlying molecular basis remains elusive. Here, we demonstrated that liver kinase B1 (Lkb1), a key bioenergetic sensor, is involved in CD11c+ cell-mediated immune responses in diet-induced obesity. Loss of Lkb1 in CD11c+ cells results in obesity resistance but lower glucose tolerance, which accompanies tissue-specific immune abnormalities. The accumulation and CD80's expression of Lkb1 deficient adipose-tissue specific dendritic cells but not macrophages is restrained. Additionally, the balance of IL-17A and IFN-γ remarkably tips towards the latter in fat T cells and CD11c- macrophages. Mechanistically, IFN-γ promotes apoptosis of preadipocytes and inhibits their adipogenesis while IL-17A promotes the adipogenesis in vitro, which might account in part for the fat gain resistant phenotype. In summary, these findings reveal that Lkb1 is essential for fat CD11c+ dendritic cells responding to HFD exposure and provides new insights into the IL-17A/IFN-γ balance in HFD-induced obesity.

  View details for DOI 10.1007/s00018-023-04707-w

  View details for PubMedID 36781473

  View details for PubMedCentralID PMC9925521

• Alveolar macrophage-derived NRP2 curtails lung injury while boosting host defense in bacterial pneumonia JOURNAL OF LEUKOCYTE BIOLOGY Wang, B., Guo, W., Qiu, C., Sun, Y., Zhao, C., Wu, C., Lai, X., Feng, X. 2022; 112 (3): 499-512

  Abstract

  Clearance of airway intruders by immune cells is required to resolve infectious pneumonia. However, the molecular mechanisms underlying this process remain elusive. Here, we demonstrated that alveolar macrophage (AM)-derived neuropilin 2 (NRP2) plays an essential role in controlling severe pneumonia by enhancing microbial clearance. Mice with conditional deletion of the NRP2 gene in AM had persistent bacteria, uncontrolled neutrophil influx, and decreased survival during Escherichia coli-induced pneumonia. In vitro assays demonstrated that NRP2 could bind to CD11b+ Ly6Glo/+ neutrophils and promote their capacities in phagocytosis and killing of bacteria, which is partially contributed to the increased expression of TLR4 and TNF-a. These findings collectively revealed that AM-derived NRP2 protects the lungs from unwanted injury by promoting the clearance of invading pathogens. This study might provide a promising diagnostic biomarker and therapeutic target for severe pneumonia.

  View details for DOI 10.1002/JLB.4A1221-770R

  View details for Web of Science ID 000783166200001

  View details for PubMedID 35435271

• Single-cell transcriptomic analysis reveals disparate effector differentiation pathways in human T-reg compartment NATURE COMMUNICATIONS Luo, Y., Xu, C., Wang, B., Niu, Q., Su, X., Bai, Y., Zhu, S., Zhao, C., Sun, Y., Wang, J., Liu, M., Sun, X., Song, G., Cui, H., Chen, X., Huang, H., Wang, H., Han, M., Jiang, E., Shi, L., Feng, X. 2021; 12 (1): 3913

  Abstract

  Human FOXP3+ regulatory T (Treg) cells are central to immune tolerance. However, their heterogeneity and differentiation remain incompletely understood. Here we use single-cell RNA and T cell receptor sequencing to resolve Treg cells from healthy individuals and patients with or without acute graft-versus-host disease (aGVHD) who undergo stem cell transplantation. These analyses, combined with functional assays, separate Treg cells into naïve, activated, and effector stages, and resolve the HLA-DRhi, LIMS1hi, highly suppressive FOXP3hi, and highly proliferative MKI67hi effector subsets. Trajectory analysis assembles Treg subsets into two differentiation paths (I/II) with distinctive phenotypic and functional programs, ending with the FOXP3hi and MKI67hi subsets, respectively. Transcription factors FOXP3 and SUB1 contribute to some Path I and Path II phenotypes, respectively. These FOXP3hi and MKI67hi subsets and two differentiation pathways are conserved in transplanted patients, despite having functional and migratory impairments under aGVHD. These findings expand the understanding of Treg cell heterogeneity and differentiation and provide a single-cell atlas for the dissection of Treg complexity in health and disease.

  View details for DOI 10.1038/s41467-021-24213-6

  View details for Web of Science ID 000668769000012

  View details for PubMedID 34162888

  View details for PubMedCentralID PMC8222404

• Control of T-reg cell homeostasis and immune equilibrium by Lkb1 in dendritic cells NATURE COMMUNICATIONS Chen, S., Fang, L., Guo, W., Zhou, Y., Yu, G., Li, W., Dong, K., Liu, J., Luo, Y., Wang, B., Li, Z., Zhao, C., Sun, Z., Shen, Y., Leng, Q., Zhou, D., Han, Z., Huang, H., Ren, H., Xu, G., Feng, X. 2018; 9: 5298

  Abstract

  To balance immunity and tolerance, the endogenous pool of Foxp3+ regulatory T (Treg) cells is tightly controlled, but the underlying mechanisms of this control remain poorly understood. Here we show that the number of Treg cells is negatively regulated by the kinase Lkb1 in dendritic cells (DCs). Conditional knockout of the Lkb1 gene in DCs leads to excessive Treg cell expansion in multiple organs and dampens antigen-specific T cell immunity. Lkb1-deficient DCs are capable of enhancing, compared with wild-type DCs, Treg cell proliferation via cell-cell contact involving the IKK/IKBα-independent activation of the NF-κB/OX40L pathway. Intriguingly, treating wild-type mice with lipopolysaccharide selectively depletes Lkb1 protein in DCs, resulting in Treg cell expansion and suppressed inflammatory injury upon subsequent challenge. Loss of Lkb1 does not obviously upregulate proinflammatory molecules expression on DCs. We thus identify Lkb1 as a regulatory switch in DCs for controlling Treg cell homeostasis, immune response and tolerance.

  View details for DOI 10.1038/s41467-018-07545-8

  View details for Web of Science ID 000453057400004

  View details for PubMedID 30546010

  View details for PubMedCentralID PMC6294005

• Spatial Transcriptomics Analysis Reveals that CCL17 and CCL22 are Robust Indicators of a Suppressive Immune Environment in Angioimmunoblastic T Cell Lymphoma (AITL) Front. Biosci. (Landmark Ed) Du, J., Qiu, C., Li, W., Wang, B., Han, X., Lin, S., Fu, ., Hou, J., Huang, Z. 2022; 27 (9): 270

  Abstract

  T cell lymphoma is a complex and highly aggressive clinicopathological entity with a poor outcome. The angioimmunoblastic T-cell lymphoma (AITL) tumor immune microenvironment is poorly investigated.Here, to the best of our knowledge, spatial transcriptomics was applied for the first time to study AITL.Using this method, we observed that AITL was surrounded by cells bearing immune-suppressive markers. CCL17 and CCL22, the dominant ligands for CCR4, were up-regulated, while the expression of natural killer (NK) cell and CD8+ cytotoxic T lymphocyte (CTL) markers decreased. Colocalization of Treg cells with the CD4+ TFH-GC region was also deduced from the bioinformatic analysis. The results obtained with spatial transcriptomics confirm that AITL has a suppressive immune environment. Chemotherapy based on the CHOP regimen (cyclophosphamide, doxorubicin, vincristine plus prednisone) induced complete remission (CR) in this AITL patient. However, the duration of remission (DoR) remains a concern.This study demonstrates that AITL has an immune suppressive environment and suggests that anti-CCR4 therapy could be a promising treatment for this lethal disease.

  View details for DOI 10.31083/j.fbl2709270