Wei Su

All Publications

• CXCR6 orchestrates brain CD8+ T cell residency and limits mouse Alzheimer's disease pathology. Nature immunology Su, W., Saravia, J., Risch, I., Rankin, S., Guy, C., Chapman, N. M., Shi, H., Sun, Y., Kc, A., Li, W., Huang, H., Lim, S. A., Hu, H., Wang, Y., Liu, D., Jiao, Y., Chen, P. C., Soliman, H., Yan, K. K., Zhang, J., Vogel, P., Liu, X., Serrano, G. E., Beach, T. G., Yu, J., Peng, J., Chi, H. 2023

  Abstract

  Neurodegenerative diseases, including Alzheimer's disease (AD), are characterized by innate immune-mediated inflammation, but functional and mechanistic effects of the adaptive immune system remain unclear. Here we identify brain-resident CD8+ T cells that coexpress CXCR6 and PD-1 and are in proximity to plaque-associated microglia in human and mouse AD brains. We also establish that CD8+ T cells restrict AD pathologies, including β-amyloid deposition and cognitive decline. Ligand-receptor interaction analysis identifies CXCL16-CXCR6 intercellular communication between microglia and CD8+ T cells. Further, Cxcr6 deficiency impairs accumulation, tissue residency programming and clonal expansion of brain PD-1+CD8+ T cells. Ablation of Cxcr6 or CD8+ T cells ultimately increases proinflammatory cytokine production from microglia, with CXCR6 orchestrating brain CD8+ T cell-microglia colocalization. Collectively, our study reveals protective roles for brain CD8+ T cells and CXCR6 in mouse AD pathogenesis and highlights that microenvironment-specific, intercellular communication orchestrates tissue homeostasis and protection from neuroinflammation.

  View details for DOI 10.1038/s41590-023-01604-z

  View details for PubMedID 37679549

  View details for PubMedCentralID 8439173

• PTEN directs developmental and metabolic signaling for innate-like T cell fate and tissue homeostasis. Nature cell biology Blanco, D. B., Chapman, N. M., Raynor, J. L., Xu, C., Su, W., Kc, A., Li, W., Lim, S. A., Schattgen, S., Shi, H., Risch, I., Sun, Y., Dhungana, Y., Kim, Y., Wei, J., Rankin, S., Neale, G., Thomas, P. G., Yang, K., Chi, H. 2022; 24 (11): 1642-1654

  Abstract

  Phosphatase and tensin homologue (PTEN) is frequently mutated in human cancer, but its roles in lymphopoiesis and tissue homeostasis remain poorly defined. Here we show that PTEN orchestrates a two-step developmental process linking antigen receptor and IL-23-Stat3 signalling to type-17 innate-like T cell generation. Loss of PTEN leads to pronounced accumulation of mature IL-17-producing innate-like T cells in the thymus. IL-23 is essential for their accumulation, and ablation of IL-23 or IL-17 signalling rectifies the reduced survival of female PTEN-haploinsufficient mice that model human patients with PTEN mutations. Single-cell transcriptome and network analyses revealed the dynamic regulation of PTEN, mTOR and metabolic activities that accompanied type-17 cell programming. Furthermore, deletion of mTORC1 or mTORC2 blocks PTEN loss-driven type-17 cell accumulation, and this is further shaped by the Foxo1 and Stat3 pathways. Collectively, our study establishes developmental and metabolic signalling networks underpinning type-17 cell fate decisions and their functional effects at coordinating PTEN-dependent tissue homeostasis.

  View details for DOI 10.1038/s41556-022-01011-w

  View details for PubMedID 36302969

  View details for PubMedCentralID PMC10080469

• Lipid metabolism in T cell signaling and function. Nature chemical biology Lim, S. A., Su, W., Chapman, N. M., Chi, H. 2022; 18 (5): 470-481

  Abstract

  T cells orchestrate adaptive immunity against pathogens and other immune challenges, but their dysfunction can also mediate the pathogenesis of cancer and autoimmunity. Metabolic adaptation in response to immunological and microenvironmental signals contributes to T cell function and fate decision. Lipid metabolism has emerged as a key regulator of T cell responses, with selective lipid metabolites serving as metabolic rheostats to integrate environmental cues and interplay with intracellular signaling processes. Here, we discuss how extracellular, de novo synthesized and membrane lipids orchestrate T cell biology. We also describe the roles of lipids as regulators of intracellular signaling at the levels of transcriptional, epigenetic and post-translational regulation in T cells. Finally, we summarize therapeutic targeting of lipid metabolism and signaling, and conclude with a discussion of important future directions. Understanding the molecular and functional interplay between lipid metabolism and T cell biology will ultimately inform therapeutic intervention for human disease.

  View details for DOI 10.1038/s41589-022-01017-3

  View details for PubMedID 35484263

  View details for PubMedCentralID 8842882

• CRISPR screens unveil signal hubs for nutrient licensing of T cell immunity. Nature Long, L., Wei, J., Lim, S. A., Raynor, J. L., Shi, H., Connelly, J. P., Wang, H., Guy, C., Xie, B., Chapman, N. M., Fu, G., Wang, Y., Huang, H., Su, W., Saravia, J., Risch, I., Wang, Y. D., Li, Y., Niu, M., Dhungana, Y., Kc, A., Zhou, P., Vogel, P., Yu, J., Pruett-Miller, S. M., Peng, J., Chi, H. 2021; 600 (7888): 308-313

  Abstract

  Nutrients are emerging regulators of adaptive immunity1. Selective nutrients interplay with immunological signals to activate mechanistic target of rapamycin complex 1 (mTORC1), a key driver of cell metabolism2-4, but how these environmental signals are integrated for immune regulation remains unclear. Here we use genome-wide CRISPR screening combined with protein-protein interaction networks to identify regulatory modules that mediate immune receptor- and nutrient-dependent signalling to mTORC1 in mouse regulatory T (Treg) cells. SEC31A is identified to promote mTORC1 activation by interacting with the GATOR2 component SEC13 to protect it from SKP1-dependent proteasomal degradation. Accordingly, loss of SEC31A impairs T cell priming and Treg suppressive function in mice. In addition, the SWI/SNF complex restricts expression of the amino acid sensor CASTOR1, thereby enhancing mTORC1 activation. Moreover, we reveal that the CCDC101-associated SAGA complex is a potent inhibitor of mTORC1, which limits the expression of glucose and amino acid transporters and maintains T cell quiescence in vivo. Specific deletion of Ccdc101 in mouse Treg cells results in uncontrolled inflammation but improved antitumour immunity. Collectively, our results establish epigenetic and post-translational mechanisms that underpin how nutrient transporters, sensors and transducers interplay with immune signals for three-tiered regulation of mTORC1 activity and identify their pivotal roles in licensing T cell immunity and immune tolerance.

  View details for DOI 10.1038/s41586-021-04109-7

  View details for PubMedID 34795452

  View details for PubMedCentralID PMC8887674

• Lipid signalling enforces functional specialization of Treg cells in tumours. Nature Lim, S. A., Wei, J., Nguyen, T. M., Shi, H., Su, W., Palacios, G., Dhungana, Y., Chapman, N. M., Long, L., Saravia, J., Vogel, P., Chi, H. 2021; 591 (7849): 306-311

  Abstract

  Regulatory T cells (Treg cells) are essential for immune tolerance1, but also drive immunosuppression in the tumour microenvironment2. Therapeutic targeting of Treg cells in cancer will therefore require the identification of context-specific mechanisms that affect their function. Here we show that inhibiting lipid synthesis and metabolic signalling that are dependent on sterol-regulatory-element-binding proteins (SREBPs) in Treg cells unleashes effective antitumour immune responses without autoimmune toxicity. We find that the activity of SREBPs is upregulated in intratumoral Treg cells. Moreover, deletion of SREBP-cleavage-activating protein (SCAP)-a factor required for SREBP activity-in these cells inhibits tumour growth and boosts immunotherapy that is triggered by targeting the immune-checkpoint protein PD-1. These effects of SCAP deletion are associated with uncontrolled production of interferon-γ and impaired function of intratumoral Treg cells. Mechanistically, signalling through SCAP and SREBPs coordinates cellular programs for lipid synthesis and inhibitory receptor signalling in these cells. First, de novo fatty-acid synthesis mediated by fatty-acid synthase (FASN) contributes to functional maturation of Treg cells, and loss of FASN from Treg cells inhibits tumour growth. Second, Treg cells in tumours show enhanced expression of the PD-1 gene, through a process that depends on SREBP activity and signals via mevalonate metabolism to protein geranylgeranylation. Blocking PD-1 or SREBP signalling results in dysregulated activation of phosphatidylinositol-3-kinase in intratumoral Treg cells. Our findings show that metabolic reprogramming enforces the functional specialization of Treg cells in tumours, pointing to new ways of targeting these cells for cancer therapy.

  View details for DOI 10.1038/s41586-021-03235-6

  View details for PubMedID 33627871

  View details for PubMedCentralID PMC8168716

• Protein Prenylation Drives Discrete Signaling Programs for the Differentiation and Maintenance of Effector Treg Cells. Cell metabolism Su, W., Chapman, N. M., Wei, J., Zeng, H., Dhungana, Y., Shi, H., Saravia, J., Zhou, P., Long, L., Rankin, S., Kc, A., Vogel, P., Chi, H. 2020; 32 (6): 996-1011.e7

  Abstract

  Effector regulatory T (eTreg) cells are essential for immune tolerance and depend upon T cell receptor (TCR) signals for generation. The immunometabolic signaling mechanisms that promote the differentiation and maintenance of eTreg cells remain unclear. Here, we show that isoprenoid-dependent posttranslational lipid modifications dictate eTreg cell accumulation and function by intersecting with TCR-induced intracellular signaling. We find that isoprenoids are essential for activated Treg cell suppressive activity, and Treg cell-specific deletion of the respective farnesylation- and geranylgeranylation-promoting enzymes Fntb or Pggt1b leads to the development of fatal autoimmunity, associated with reduced eTreg cell accumulation. Mechanistically, Fntb promotes eTreg cell maintenance by regulating mTORC1 activity and ICOS expression. In contrast, Pggt1b acts as a rheostat of TCR-dependent transcriptional programming and Rac-mediated signaling for establishment of eTreg cell differentiation and immune tolerance. Therefore, our results identify bidirectional metabolic signaling, specifically between immunoreceptor signaling and metabolism-mediated posttranslational lipid modifications, for the differentiation and maintenance of eTreg cells.

  View details for DOI 10.1016/j.cmet.2020.10.022

  View details for PubMedID 33207246

  View details for PubMedCentralID PMC7887758

• Phase-separated condensate-aided enrichment of biomolecular interactions for high-throughput drug screening in test tubes. The Journal of biological chemistry Zhou, M., Li, W., Li, J., Xie, L., Wu, R., Wang, L., Fu, S., Su, W., Hu, J., Wang, J., Li, P. 2020; 295 (33): 11420-11434

  Abstract

  Modification-dependent and -independent biomolecular interactions, including protein-protein, protein-DNA/RNA, protein-sugar, and protein-lipid interactions, play crucial roles in all cellular processes. Dysregulation of these biomolecular interactions or malfunction of the associated enzymes results in various diseases; therefore, these interactions and enzymes are attractive targets for therapies. High-throughput screening can greatly facilitate the discovery of drugs for these targets. Here, we describe a biomolecular interaction detection method, called phase-separated condensate-aided enrichment of biomolecular interactions in test tubes (CEBIT). The readout of CEBIT is the selective recruitment of biomolecules into phase-separated condensates harboring their cognate binding partners. We tailored CEBIT to detect various biomolecular interactions and activities of biomolecule-modifying enzymes. Using CEBIT-based high-throughput screening assays, we identified known inhibitors of the p53/MDM2 (MDM2) interaction and of the histone methyltransferase, suppressor of variegation 3-9 homolog 1 (SUV39H1), from a compound library. CEBIT is simple and versatile, and is likely to become a powerful tool for drug discovery and basic biomedical research.

  View details for DOI 10.1074/jbc.RA120.012981

  View details for PubMedID 32461254

  View details for PubMedCentralID PMC7450138

• Discrete roles and bifurcation of PTEN signaling and mTORC1-mediated anabolic metabolism underlie IL-7-driven B lymphopoiesis. Science advances Zeng, H., Yu, M., Tan, H., Li, Y., Su, W., Shi, H., Dhungana, Y., Guy, C., Neale, G., Cloer, C., Peng, J., Wang, D., Chi, H. 2018; 4 (1): eaar5701

  Abstract

  Interleukin-7 (IL-7) drives early B lymphopoiesis, but the underlying molecular circuits remain poorly understood, especially how Stat5 (signal transducer and activator of transcription 5)-dependent and Stat5-independent pathways contribute to this process. Combining transcriptome and proteome analyses and mouse genetic models, we show that IL-7 promotes anabolic metabolism and biosynthetic programs in pro-B cells. IL-7-mediated activation of mTORC1 (mechanistic target of rapamycin complex 1) supported cell proliferation and metabolism in a Stat5-independent, Myc-dependent manner but was largely dispensable for cell survival or Rag1 and Rag2 gene expression. mTORC1 was also required for Myc-driven lymphomagenesis. PI3K (phosphatidylinositol 3-kinase) and mTORC1 had discrete effects on Stat5 signaling and independently controlled B cell development. PI3K was actively suppressed by PTEN (phosphatase and tensin homolog) in pro-B cells to ensure proper IL-7R expression, Stat5 activation, heavy chain rearrangement, and cell survival, suggesting the unexpected bifurcation of the classical PI3K-mTOR signaling. Together, our integrative analyses establish IL-7R-mTORC1-Myc and PTEN-mediated PI3K suppression as discrete signaling axes driving B cell development, with differential effects on IL-7R-Stat5 signaling.

  View details for DOI 10.1126/sciadv.aar5701

  View details for PubMedID 29399633

  View details for PubMedCentralID PMC5792226

• Iodobacter limnosediminis sp. nov., isolated from Arctic lake sediment. International journal of systematic and evolutionary microbiology Su, W., Zhou, Z., Jiang, F., Chang, X., Liu, Y., Wang, S., Kan, W., Xiao, M., Shao, M., Peng, F., Fang, C. 2013; 63 (Pt 4): 1464-1470

  Abstract

  A Gram-reaction-negative, motile, non-violet-pigmented, rod-shaped bacterial strain, designated E1(T), was isolated from Arctic lake sediment. Growth occurred at 4 °C-28 °C (optimum, 18 °C), at pH 4-11(optimum, 9-10) and in the presence of 0-1 % (w/v) NaCl. The taxonomic position of E1(T) was analysed using a polyphasic approach. Strain E1(T) exhibited 16S rRNA gene sequence similarity value of 98.1 % with respect to the type strain of Iodobacter fluviatilis, but no more than 93 % with the type strains of other recognized species. A further DNA-DNA hybridization experiment was conducted, which demonstrated unambiguously that strain E1(T) was distinct from I. fluviatilis ATCC 33051(T) (51.3 % relatedness). The DNA G+C content of strain E1(T) was 52.3 mol%. Chemotaxonomic data [Q-8 as the monospecific respiratory quinone and summed feature 3 (C16 : 1ω7c and/or C16 : 1ω6c, 56.1 %) and C16 : 0 (18.8 %) as the major cellular fatty acids] supported the affiliation of strain E1(T) to the genus Iodobacter. However, the results of physiological and biochemical tests allowed phenotypic differentiation of strain E1(T) from I. fluviatilis ATCC 33051(T). On the basis of phenotypic and genotypic properties, strain E1(T) represents a novel species of genus Iodobacter, for which the name Iodobacter limnosediminis sp. nov. is proposed. The type strain is E1(T) ( = CCTCC AB 2010224(T) = NRRL B-59456(T)).

  View details for DOI 10.1099/ijs.0.039982-0

  View details for PubMedID 22888184