About

Jonathan D Bui is a Clinical Professor in the Neurosciences School at UC San Diego. His research involves various aspects of neurology, with publications covering topics such as epileptic spasms, biofluid analysis, neuroimmunology, and neuroimaging techniques. His work includes studies on high-dose prednisolone failure in epileptic spasms, biofluid and tissue analysis using high-throughput proteomics, and immune-mediated encephalitis. He has contributed to understanding neurological autoimmunity, neurodegenerative diseases like early-onset Alzheimer's, and the application of magnetic resonance microscopy in neural tissue analysis. His research also encompasses the evaluation of microcapsules via MRI, the pathophysiology of central neurogenic hyperventilation, and the effects of various pharmacological agents on neural tissues. Bui's work is characterized by a focus on advanced imaging, neuroimmunology, and translational neurology, with numerous publications derived from MEDLINE/PubMed and other sources.

Research topics

• Biology
• Immunology
• Genetics
• Cancer research
• Medicine
• Pharmacology
• Bioinformatics
• Molecular biology
• Pathology
• Internal medicine

Selected publications

• Abstract 2211: STAT1 and STAT3 cooperatively control cancer stem cell (CSC) fate and IFNγ-dependent CSC maintenance.

  Cancer Research · 2026-04-03

  article

  Abstract Background: Cancer stem cells (CSCs) are a rare tumor cell subset with self-renewal and differentiation capacity that drives tumor initiation, heterogeneity, metastasis, and therapy resistance. Interferon-γ (IFNγ) has been implicated in regulating CSC fate, but its effects are highly context dependent. How the intrinsic balance between opposing IFNγ pathway effectors such as STAT1 and STAT3 shapes CSC properties remains poorly understood. Methods: Breast (4T1, PY230) and sarcoma (F244, F236, H74) cell lines were exposed to high acute or persistent IFNγ stimulation. STAT1/STAT3 were deleted via CRISPR-Cas9. Retroviral transfection was used to restore STAT1 in STAT1-deficient H74 sarcoma cells. CSC induction was monitored using molecular and sphere formation assays for in vitro and in vivo experiments. Bioinformatic analyses include single-cell and bulk-RNA sequencing from public databases of human breast cancer. Results: In this study, we found that cancer cell lines with higher expression of stem-cell-associated markers at baseline tend to have a lower STAT1/ STAT3 ratio and/or constitutive STAT3 activation. Exposure to acute high dose of IFNγ or persistent exposure to IFNγ led a progressive increase of CSC-associated genes (e.g. Zeb1, Bst2, Tert). STAT1 depletion favored CSC induction, while STAT3 loss led to increased cell death both with or without IFNγ stimulation. Interestingly, combined STAT1/STAT3 depletion markedly increased sphere size independently of IFNγ treatment, indicating that those two transcription factors may cooperate to restrain CSC proliferation. In vivo, STAT1-deficient H74 sarcoma cell line exhibited accelerated tumor progression and CSC induction in an IFNγ-dependent manner. By contrast, restoration of STAT1 completely abrogated H74 tumor growth in immunocompetent but not immunodeficient mice, confirming that STAT1 limits CSC induction by sensitizing tumor cells to immune-mediated cytotoxicity. Finally, single-cell RNAseq of human breast cancer cells revealed an inverse correlation between STAT1 and STAT3 expressions. STAT1-negative tumor cells with high IFNγ score were enriched in EMT- and apoptosis-related programs. Consistently, IFNγhi/STAT3hi breast tumors exhibited a stronger EMT signature and were associated with poorer clinical outcomes compared with IFNγhi/STAT3lo tumors. Conclusions: Modulating the STAT1/STAT3 balance can suppress CSC expansion and preserve tumor cell vulnerability to immune-mediated killing. STAT1-sufficient tumors respond to IFNγ typically by increasing immunogenicity and limiting CSC potential, whereas STAT1-deficient tumors respond to IFNγ by increasing CSC properties. These results suggest that STAT1 serves as a toggle for anti- and pro-tumor effects of IFNγ. Citation Format: Sophia Hidalgo, Anushka Poola, Yipeng Zhang, Rachel Zhou, Kourosh Kouhmareh, Jack D. Bui, Magalie Dosset. STAT1 and STAT3 cooperatively control cancer stem cell (CSC) fate and IFNγ-dependent CSC maintenance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2211.

  PublisherDOI

• Human PD1 verus mouse PD1 - how different are they? 3290

  The Journal of Immunology · 2025-11-01

  articleOpen accessSenior author

  Abstract Description Mechanistic understanding of the inhibitory immunoreceptor PD1 is largely based on mouse models, but human and mouse PD1 orthologs exhibit only 59.6% identity in amino acid sequences. We show that human PD1 is more inhibitory than mouse PD1 due to stronger interactions with the ligands PDL1 and PDL2 and with the effector phosphatase Shp2. A novel motif highly conserved among PD1 orthologs in vertebrates except in rodents is primarily responsible for the differential Shp2 recruitment. Evolutionary analysis suggested that rodent PD1 orthologs uniquely underwent functional relaxation, particularly during the K-Pg boundary. Humanization of the PD1 intracellular domain disrupted the anti-tumor activity of mouse T cells while increasing the magnitude of anti-PD1 response. Together, our study uncovers species-specific features of the PD1 pathway, with implications to PD1 evolution and differential anti-PD(L)1 responses in mouse models and human patients. Funding Sources Supported by R37 CA239072 from the National Institute of Health, the Hartwell Foundation, Human Frontiers Science Program and JST PRESTO grant (JPMJPR22EB) Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)

  PublisherOA PDFDOI

• Identification Of Protein Cargo in Extracellular Vesicles from Macrophages in Progressing and Regressing Tumors

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-06

  preprintOpen accessSenior authorCorresponding

  Exosomes are extracellular vesicles (EVs) that carry bioactive molecules from a cell of origin and may alter gene expression of the acceptor cell via binding to cell surface receptors and/or delivering their cargo into the cell. Tumor-associated macrophages (TAMs) can increase or decrease tumor growth through various mechanisms, but the impact of TAM-EVs on tumors has been difficult to elucidate due to challenges in isolating and culturing TAMs for EV purification. In this study, we set out to uncover the protein identities within EVs from TAMs in progressing and regressing tumors, thereby uncovering EV proteins' roles in TAM-tumor crosstalk. TAMs were purified from tumors using magnetic bead isolation and cultured for up to 9 days. TAMs from regressing tumors were found to be more M1-like by high expression of major histocompatibility complex (MHC) class II, while TAMs from progressing tumors are more M2-like (low expression of MHC class II). Long-term in vitro culture of TAMs resulted in reduced expression of MHC class II. EVs were harvested from plated TAMs, and EV proteins were identified by mass spectrometry and compared to EV proteins from bone marrow-derived macrophages (BMDMs). Unsupervised hierarchical clustering studies revealed that proteins from TAM-EVs converge based on their in vitro culture duration rather than their tumor origin. Signature proteins in TAM-EVs were characterized, with the identification of galectin-3-binding protein as a signature protein present in EVs from M1-like BMDMs and regressor macrophages. Finally, immunostimulatory pathways were identified in progressor-TAM-EVs through protein-protein interaction network analysis.

  PublisherDOI

• Mammary tissue microbiome analysis in PyMT mice reveals Methylobacteria as a commensal organism with potential therapeutic applications

  Translational Oncology · 2025-06-25 · 1 citations

  articleOpen accessCorresponding

  • Gut, tumor, and normal breast microbiome were investigated in the PyMT mouse model of breast cancer. • Mouse gut microbiome is not associated with presence or absence of breast cancer. • Tumor (PyMT+) microbiome is distinct from the normal (PYMT-) mouse mammary tissue microbiome. • Comparison of relative abundances at the bacterial genus level showed that Coprococcus and Ralstonia were associated with tumor tissue, whereas Methylobacterium, Tepidimonas , and Staphylococcus were associated with normal tissue. • Methylobacterium limited breast cancer growth in a mouse breast cancer model. Studies have reported differences in specific bacteria comparing the tissue microbiome in human breast cancer versus normal breast tissue, prompting hypotheses for potential therapies or theragnosis. To test these hypotheses using controlled experiments animal models are needed. Therefore, we investigated the microbiome in the gut and mammary tissue in a mouse model of breast cancer. C57BL/6 mice expressing the polyoma middle T antigen in the mammary gland (PyMT) develop spontaneous multifocal breast tumors. Microbiota in the gut and mammary tissue were studied prior to and after development of mammary gland tumors by amplicon and shotgun DNA sequencing. In parallel, RNA sequencing was performed on tumor and normal tissue to measure differences in gene expression associated with breast cancer. Bacteria identified in these studies were administered to mice to test their effects on cancer progression. Bacterial community composition in the gut of healthy or tumor-bearing mice showed wide fluctuation over time and did not organize into discrete clusters. In tumor versus healthy mammary gland tissue, relative abundances of six bacteria were significantly different: Ralstonia, Methylobacterium, Pelomonas, Staphylococcus and Tepidimonas. Methlyobacterium sequences were significantly higher (PERMANOVA, P = 0.013) in healthy tissue when compared to tumor, leading to a hypothesis that Methylobacterium may promote health. When co-transplanted with breast tumor cells, Methylobacterium reduced growth in immune competent mice. Here we describe the gut and mammary tissue microbial composition of healthy and breast tumor-bearing animals, identifying Methylobacterium sp as a commensal bacteria that might have therapeutic potential to reduce breast cancer progression.

  PublisherDOI

• BPS2025 - Differential biophysical and functional properties of human vs. mouse PD1

  Biophysical Journal · 2025-02-01

  article
  PublisherDOI

• Interferon responsiveness reporter mice demonstrate memory of interferon exposure by hematopoietic stem progenitor cells 3091

  The Journal of Immunology · 2025-11-01

  articleOpen access1st authorCorresponding

  Abstract Description Trained immunity occurs after an inflammatory reaction induces epigenetic changes in innate immune cells, leading to altered responses upon subsequent. The innate cells that might adapt during trained immunity include natural killer (NK) cells, monocytes/macrophages, and even hematopoietic stem progenitor cells (HSPCs). To track interferon (IFN) exposure, we used MX1-CRE mice, which induce the Cre recombinase upon exposure to Type I IFN, we track and lineage trace IFN-experience with an LSL-tdTRed (TR) reporter transgene. In these dual transgenic mice, IFN-exposed cells permanently express TR, allowing for easy tracking. IFN-naïve cells in the mice remain unlabeled. We found that hematopoietic stem progenitor cells (HSPCs) had IFN-exposure even without an inflammatory stimulus, consistent with the role of IFN in hematopoiesis. Notably, the exposure of HSPCs to IFN seemed to be “remembered” by their TR-labeled progeny. Specifically natural killer (NK) cells and macrophages descended from TR-expressing HSPCs (IFN-experienced) had greater activity than their IFN-naïve counterparts from the same animal. We further demonstrate that the microbiome could impact on the levels of IFN-experienced cells. Gene expression studies define a unique signature for IFN experience in NK and macrophage lineages. We conclude that HSPCs may “remember” exposure to IFN during normal hematopoiesis and pass this memory to their descendants, leading to altered activities. Funding Sources The Hartwell Foundation Topic Categories Hematopoiesis and Immune System Development (HEM)

  PublisherOA PDFDOI

• RGI-2001 for the prophylaxis of acute graft-versus-host disease after allogeneic HCT

  Blood · 2025-07-18 · 4 citations

  article

  ABSTRACT: RGI-2001, a glycolipid that binds CD1d receptor of antigen-presenting cells, can activate invariant natural killer T (NKT) cells and stimulate cytokine-dependent proliferation of regulatory T cells (Tregs). This open-label, multicenter phase 2b trial evaluated the safety and efficacy of RGI-2001 in combination with standard graft-versus-host disease (GVHD) prophylaxis in participants receiving myeloablative allogeneic hematopoietic cell transplantation (HCT). RGI-2001 was infused at a dose of 100 μg/kg for 6 weekly doses. The primary end point was grade 2 to 4 acute GVHD by day 100. A total of 49 participants received RGI-2001 in combination with tacrolimus and methotrexate. RGI-2001 was well tolerated, with no serious infusion reactions. Sixteen participants experienced grade ≥3 treatment-related adverse events, including decreased appetite, leukopenia, thrombocytopenia, and stomatitis. The cumulative incidence of grade 2 to 4 and 3 to 4 acute GVHD were 24.9% and 4.1%, respectively. Compared with the controls from the Center for International Blood and Marrow Research Transplant registry, participants receiving RGI-2001 experienced superior clinical outcomes, including day-180 grade 2 to 4 acute GVHD-free survival (70.8% vs 50.7%; adjusted hazard ratio, 0.45; 95% confidence interval, 0.30-0.68). Increasing NKT and Treg populations were observed after HCT, consistent with the proposed action of RGI-2001. In conclusion, RGI-2001 was well tolerated and was associated with low rates of acute GVHD and encouraging survival after myeloablative HCT. These results support strategies that target NKT and Treg cell populations to augment immunologic changes in allogeneic HCT recipients. This trial was registered at www.clinicaltrials.gov as #NCT04014790.

  PublisherDOI

• Mammary Tissue Microbiome Analysis in Pymt Mice Reveals Methylobacteria as a Commensal Organism with Potential Therapeutic Applications

  SSRN Electronic Journal · 2025-01-01

  preprintOpen access
  PublisherDOI

• Functional differences between rodent and human PD-1 linked to evolutionary divergence

  Science Immunology · 2025-01-03 · 29 citations

  articleOpen accessCorresponding

  Mechanistic understanding of the inhibitory immunoreceptor PD-1 is largely based on mouse models, but human and mouse PD-1 share only 59.6% amino acid identity. Here, we found that human PD-1 is more inhibitory than mouse PD-1, owing to stronger interactions with the ligands PD-L1 and PD-L2 and more efficient recruitment of the effector phosphatase Shp2. In a mouse melanoma model with adoptively transferred T cells, humanization of a PD-1 intracellular domain disrupted the antitumor activity of CD8 + T cells and increased the magnitude of anti–PD-1 response. We identified a motif highly conserved across vertebrate PD-1 orthologs, absent in rodents, as a key determinant for differential Shp2 recruitment. Evolutionary analysis suggested that PD-1 underwent a rodent lineage–specific functional attenuation during evolution. Together, our study uncovers species-specific features of the PD-1 pathway, with implications for PD-1 evolution and differential anti–PD-(L)1 responses in mouse models and human patients.

  PublisherOA PDFDOI

• Mutant prion protein enhances NMDA receptor activity, activates PKC, and triggers rapid excitotoxicity in mice

  Journal of Clinical Investigation · 2025-04-04 · 6 citations

  articleOpen access

  Neuronal hyperexcitability precedes synapse loss in certain neurodegenerative diseases, yet the synaptic membrane interactions and downstream signaling events remain unclear. The disordered amino terminus of the prion protein (PrPC) has been implicated in aberrant signaling in prion and Alzheimer's disease. To disrupt neuronal interactions and signaling linked to the amino terminus, we CRISPR-engineered a knockin mouse expressing mutant PrPC (G92N), generating an N-linked glycosylation site between 2 functional motifs. Mice developed seizures and necrosis of hippocampal pyramidal neurons, similar to prion-infected mice and consistent with excitotoxicity. Phosphoproteomics analysis revealed phosphorylated glutamate receptors and calcium-sensitive kinases, including protein kinase C (PKC). Additionally, 92N-PrPC-expressing neurons showed persistent calcium influx as well as dendritic beading, which was rescued by an N-methyl-d-aspartate receptor (NMDAR) antagonist. Finally, survival of Prnp92N mice was prolonged by blocking active NMDAR channels. We propose that dysregulated PrPC-NMDAR-induced signaling can trigger an excitatory-inhibitory imbalance, spongiform degeneration, and neurotoxicity and that calcium dysregulation is central to PrPC-linked neurodegeneration.

  PublisherOA PDFDOI

Recent grants

• Innate anti-tumor immune responses

  NIH · $1.8M · 2011–2017

• Elucidating the regulation and function of IL-17D using reporter mice

  NIH · $434k · 2020–2023

• NIH Grant K08CA128893

  NIH · $631k · 2014

Frequent coauthors

• Emilie Gross

  59 shared

• Robert D. Schreiber

  44 shared

• Wayne M. Yokoyama

  33 shared

• Daniel Kreisel

  University of Missouri–St. Louis

  32 shared

• Kelsey A. Toth

  Washington University in St. Louis

  32 shared

• Beatriz M. Carreno

  University of Pennsylvania

  32 shared

• Ryuji Higashikubo

  32 shared

• Haris G. Vikis

  32 shared

Labs

• Jonathan Bui | UCSD ProfilesPI

Education

• Ph.D., Neurosciences

  University of California, San Diego

  2000

• M.D., Medicine

  University of California, San Diego

  1996

• B.A., Psychology

  University of California, San Diego

  1992