A5100334394- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Immune Response and Inflammation
- Ubiquitin and proteasome pathways
- Cancer Immunotherapy and Biomarkers
- CRISPR and Genetic Engineering
- Autophagy in Disease and Therapy
- RNA modifications and cancer
- Genetics, Aging, and Longevity in Model Organisms
- Vector-Borne Animal Diseases
- Single-cell and spatial transcriptomics
- Cytomegalovirus and herpesvirus research
- Immunotherapy and Immune Responses
- CAR-T cell therapy research
- Epigenetics and DNA Methylation
- Genetics and Neurodevelopmental Disorders
- Vector-borne infectious diseases
- interferon and immune responses
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Adenosine and Purinergic Signaling
- Cancer Mechanisms and Therapy
- Phagocytosis and Immune Regulation
- Nanoparticles: synthesis and applications
- Protein Degradation and Inhibitors
- Cancer Research and Treatments
The University of Texas Southwestern Medical Center
2015-2025
Weifang People's Hospital
2025
University of Science and Technology Beijing
2024
Health Commission of Jilin Province
2024
Southwestern Medical Center
2020
Howard Hughes Medical Institute
2014
University of Shizuoka
1996-2006
Multivalent molecules with repetitive structures including bacterial capsular polysaccharides and viral capsids elicit antibody responses through B cell receptor (BCR) crosslinking in the absence of T help. We report that immunization these cell–independent type 2 (TI-2) antigens causes up-regulation endogenous retrovirus (ERV) RNAs antigen-specific mouse cells. These are detected via a mitochondrial antiviral signaling protein (MAVS)–dependent RNA sensing pathway or reverse-transcribed...
Significance Adjuvants enhance adaptive immune responses, sometimes through unknown mechanisms, and can be used to augment both humoral cellular responses cancer antigens. We report the immunological effects of synthetic chemical adjuvant Diprovocim, which targets innate receptor TLR1/TLR2 in mice humans. Diprovocim displayed strong activity mice, particularly abetting responses. Immunization against a genetically engineered tumor-specific antigen, ovalbumin, when adjuvanted with inhibited...
With the wide availability of massively parallel sequencing technologies, genetic mapping has become rate limiting step in mammalian forward genetics. Here we introduce a method for real-time identification N-ethyl-N-nitrosourea-induced mutations that cause phenotypes mice. All are identified by whole exome G1 progenitor and their zygosity is established G2/G3 mice before phenotypic assessment. Quantitative qualitative traits, including lethal effects, single or multiple combined pedigrees...
Many endogenous molecules, mostly proteins, purportedly activate the Toll-like receptor 4 (TLR4)-myeloid differentiation factor-2 (MD-2) complex, innate immune for lipopolysaccharide (LPS) derived from gram-negative bacteria. However, there is no structural evidence supporting direct TLR4-MD-2 activation by ligands. Sulfatides (3-O-sulfogalactosylceramides) are natural, abundant sulfated glycolipids that have variously been shown to initiate or suppress inflammatory responses. We show here...
In a genetic screen, we identified two viable missense alleles of the essential gene Midnolin (Midn) that were associated with reductions in peripheral B cells. Causation was confirmed mice targeted deletion four six MIDN protein isoforms. expressed predominantly lymphocytes where it augmented proteasome activity. We showed purified directly stimulated 26S activity vitro manner dependent on ubiquitin-like domain and C-terminal region. MIDN-deficient cells displayed aberrant activation...
Significance Activation of Toll-like receptors by microbes or host-derived molecules triggers signaling that promotes inflammation and may contribute to the development autoimmunity. Here we show excessive innate immune (TLRs) TLR3, TLR7, TLR9 is causative for inflammatory disease in mice with mutations Smcr8 . The cellular mechanism their hyperactivation likely prolonged ligand–receptor contact lysosomes phagosomes, trafficking which regulated SMCR8-WDR41-C9ORF72 complex cells. We also...
The protein midnolin (MIDN) augments proteasome activity in lymphocytes, where it is predominantly expressed adult mice. MIDN binds both to proteasomes and substrates, but the mechanism by which facilitates substrate degradation a ubiquitin-independent manner unknown. Here, we present cryo-electron microscopy structures of substrate-engaged, MIDN-bound human two conformational states. induces conformations similarly ubiquitinated substrates using its ubiquitin-like domain bind deubiquitinase...
The protein midnolin (MIDN) augments proteasome activity in lymphocytes and dramatically facilitates the survival proliferation of B-lymphoid malignancies. MIDN binds both to proteasomes substrates, but mode interaction with is unknown, mechanism by which substrate degradation a ubiquitin-independent manner incompletely understood. Here, we present cryoelectron microscopy (cryo-EM) structures substrate-engaged, MIDN-bound human two conformational states. induces conformations similarly...
Transcriptional regulation of numerous interferon-regulated genes, including Toll-like receptor 3 (Tlr3), which encodes an innate immune sensor viral double-stranded RNA, depends on the interferon regulatory factor 1 (IRF1) and IRF2 transcription factors. We detected specific abrogation macrophage responses to polyinosinic-polycytidylic acid (poly(I:C)) resulting from three independent N-ethyl-N-nitrosourea-induced mutations in host cell C2 (Hcfc2). Hcfc2 compromised survival during...
Prkd2-dependent phosphorylation of Bcl6 inhibits T FH cell differentiation.
Significance Follicular B cells generally require T cell help to contribute adaptive immunity, producing several isotypes of immunoglobulins that carry out distinct effector functions. Two specialized subsets, marginal zone (MZ) and B-1 cells, arise from different developmental steps have They become activated produce antibodies without are the major sources plasma IgM. We identified a viable missense allele Ncstn in forward genetic screen. discovered development MZ TI antibody response, fur...
Abstract Signals emanating from the T-cell receptor (TCR), co-stimulatory receptors, and cytokine receptors each influence CD8 fate. Understanding how these signals respond to homeostatic microenvironmental cues can reveal new ways therapeutically direct function. Through forward genetic screening in mice, we discover that loss-of-function mutations LDL receptor-related protein 10 ( Lrp10 ) cause naive central memory T cells accumulate peripheral lymphoid organs. encodes a conserved cell...
Despite the availability of life-extending treatments for B cell leukemias and lymphomas, many these cancers remain incurable. Thus, development new molecular targets therapeutics is needed to expand treatment options. To identify targets, we used a forward genetic screen in mice genes required or survival lymphocytes. Here, describe
The small GTPase RABL3 is an oncogene of unknown physiological function. Homozygous knockout alleles mouse Rabl3 were embryonic lethal, but a viable hypomorphic allele (xiamen [xm]) causing in-frame deletion four amino acids from the interswitch region resulted in profound defects lymphopoiesis. Impaired lymphoid progenitor development led to deficiencies B cells, T and natural killer (NK) cells Rabl3xm/xm mice. NK exhibited impaired cytolytic activity, mice infected with cytomegalovirus...
Significance We developed software called Candidate Explorer (CE) that uses a machine-learning algorithm to identify chemically induced mutations are causative of screened phenotypes. CE determines the probability mutation will be verified as for phenotype if gene is independently targeted knockout or recreation mutation. 67 parameters from mapping data—including gene, mutation, genotype, allelism, and information—to determine Score verification probability. used evaluate ∼87,000...
We detected ENU-induced alleles of Mfsd1 (encoding the major facilitator superfamily domain containing 1 protein) that caused lymphopenia, splenomegaly, progressive liver pathology, and extramedullary hematopoiesis (EMH). MFSD1 is a lysosomal membrane-bound solute carrier protein with no previously described function in immunity. By proteomic analysis, we identified association between both GLMP (glycosylated membrane GIMAP5 (GTPase immunity-associated 5). Germline knockout , Glmp Gimap5...
Null mutations of spliceosome components or cofactors are homozygous lethal in eukaryotes, but viable hypomorphic provide an opportunity to understand the physiological impact individual splicing proteins. We describe a missense allele (F181I) Rnps1 encoding essential regulator and nonsense-mediated decay (NMD), identified mouse genetic screen for altered immune cell development. Homozygous mice displayed stem cell–intrinsic defect hematopoiesis all lineages due excessive apoptosis induced...
Adenosine monophosphate deaminase 3 (Ampd3) encodes the erythrocyte isoform of adenosine (AMP) gene family. Mutations in this have been reported humans, leading to autosomal-recessive AMP deficiency. However, mutation is considered clinically asymptomatic. Using N-ethyl-N-nitrosourea mutagenesis find mutations that affect peripheral lymphocyte populations, we identified 5 Ampd3 (Ampd3guangdong, Ampd3carson, Ampd3penasco, Ampd3taos, and Ampd3commanche) strongly correlated with a reduction...
Atopy, the overall tendency to become sensitized an allergen, is heritable but seldom ascribed mutations within specific genes. Atopic individuals develop abnormally elevated IgE responses immunization with potential allergens. To gain insight into genetic causes of atopy, we carried out a forward screen for atopy in mice.We screened mice carrying homozygous and heterozygous N-ethyl-N-nitrosourea (ENU)-induced germline aberrant antigen-specific IgG1 production response model allergen papain....
Immune checkpoint inhibitors interfere with T cell exhaustion but often fail to cure or control cancer long-term in patients. Using a genetic screen C57BL/6J mice, we discovered mutation host H2-Aa that caused strong immune-mediated resistance mouse melanomas. encodes an MHC class II α chain, and its absence mice eliminates all MHC-II expression. deficiency, specifically dendritic cells (DC), led quantitative increase type 2 conventional DC (cDC2) decrease cDC1. H2-Aa-deficient cDC2, not...
The outer surface proteins OspA and OspB genes of clinical Borrelia garinii isolates (JEM1–8) from Hokkaido, Japan were sequenced. One strain, JEM4, has a single ospA gene which is similar to European B. strains PBr (sequence homology value: 94.1%) T25 (91.2%). Five the other seven exhibit homologous C-terminus (300 bp) on both ospB (88.7–97.3%). two seem be derived five by or alterations. In phylogenetic analysis based ospA, these could classified into garinii, but formed independent...
ABSTRACT Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) is a member of the basic helix-loop-helix/PER-ARNT-SIM (bHLH/PAS) transcription factor family. ARNT2 heterodimerizes with several members family, including single-minded homolog-1 (SIM1) and neuronal PAS domain protein 4 (NPAS4), primarily in neurons central nervous system. We screened 64,424 third-generation germline mutant mice derived from N-ethyl-N-nitrosourea (ENU)-mutagenized great-grandsires for weight abnormalities....
Abstract Distinct pathways and molecules may support embryonic versus postnatal thymic epithelial cell (TEC) development maintenance. Here, we identify a mechanism by which TEC numbers function are maintained postnatally. A viable missense allele (C120Y) of Ovol2 , expressed ubiquitously or specifically in TECs, results lymphopenia, T is compromised loss medullary TECs dysfunction cortical TECs. We show that the identity aberrantly subverted towards mesenchymal state OVOL2-deficient mice....
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