Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 242

Publication Record

Connections

Histone deacetylase 3 controls a transcriptional network required for B cell maturation.
Stengel KR, Bhaskara S, Wang J, Liu Q, Ellis JD, Sampathi S, Hiebert SW
(2019) Nucleic Acids Res 47: 10612-10627
MeSH Terms: Animals, Antigens, CD19, B-Lymphocytes, Base Sequence, Cell Differentiation, Gene Expression Regulation, Gene Regulatory Networks, Histone Deacetylase Inhibitors, Histone Deacetylases, Lipopolysaccharides, Lymphocyte Activation, Mice, Inbred C57BL, Plasma Cells, Positive Regulatory Domain I-Binding Factor 1, Proto-Oncogene Proteins c-bcl-6, Repressor Proteins, Transcription, Genetic, Up-Regulation
Show Abstract · Added October 25, 2019
Histone deacetylase 3 (Hdac3) is a target of the FDA approved HDAC inhibitors, which are used for the treatment of lymphoid malignancies. Here, we used Cd19-Cre to conditionally delete Hdac3 to define its role in germinal center B cells, which represent the cell of origin for many B cell malignancies. Cd19-Cre-Hdac3-/- mice showed impaired germinal center formation along with a defect in plasmablast production. Analysis of Hdac3-/- germinal centers revealed a reduction in dark zone centroblasts and accumulation of light zone centrocytes. RNA-seq revealed a significant correlation between genes up-regulated upon Hdac3 loss and those up-regulated in Foxo1-deleted germinal center B cells, even though Foxo1 typically activates transcription. Therefore, to determine whether gene expression changes observed in Hdac3-/- germinal centers were a result of direct effects of Hdac3 deacetylase activity, we used an HDAC3 selective inhibitor and examined nascent transcription in germinal center-derived cell lines. Transcriptional changes upon HDAC3 inhibition were enriched for light zone gene signatures as observed in germinal centers. Further comparison of PRO-seq data with ChIP-seq/exo data for BCL6, SMRT, FOXO1 and H3K27ac identified direct targets of HDAC3 function including CD86, CD83 and CXCR5 that are likely responsible for driving the light zone phenotype observed in vivo.
© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.
1 Communities
0 Members
0 Resources
18 MeSH Terms
Single-cell transcriptomics reveal polyclonal memory T-cell responses in skin with positive abacavir patch test results.
Redwood AJ, Rwandamuriye F, Chopra A, Leary S, Ram R, McDonnell W, Konvinse K, White K, Pavlos R, Koelle DM, Mallal S, Phillips EJ
(2019) J Allergy Clin Immunol 144: 1413-1416.e7
MeSH Terms: Aged, Anti-HIV Agents, Arthralgia, CD8-Positive T-Lymphocytes, Dideoxynucleosides, Drug Hypersensitivity, Drug-Related Side Effects and Adverse Reactions, Gene Expression Profiling, HLA-B Antigens, Headache, Humans, Immunologic Memory, Lymphocyte Activation, Male, Myalgia, Patch Tests, Single-Cell Analysis, Skin
Added March 30, 2020
0 Communities
1 Members
0 Resources
18 MeSH Terms
A case report of clonal EBV-like memory CD4 T cell activation in fatal checkpoint inhibitor-induced encephalitis.
Johnson DB, McDonnell WJ, Gonzalez-Ericsson PI, Al-Rohil RN, Mobley BC, Salem JE, Wang DY, Sanchez V, Wang Y, Chastain CA, Barker K, Liang Y, Warren S, Beechem JM, Menzies AM, Tio M, Long GV, Cohen JV, Guidon AC, O'Hare M, Chandra S, Chowdhary A, Lebrun-Vignes B, Goldinger SM, Rushing EJ, Buchbinder EI, Mallal SA, Shi C, Xu Y, Moslehi JJ, Sanders ME, Sosman JA, Balko JM
(2019) Nat Med 25: 1243-1250
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, CD4-Positive T-Lymphocytes, Encephalitis, Female, Herpesvirus 4, Human, Humans, Immunologic Memory, Lymphocyte Activation, Male, Middle Aged, Programmed Cell Death 1 Receptor, Young Adult
Show Abstract · Added November 12, 2019
Checkpoint inhibitors produce durable responses in numerous metastatic cancers, but immune-related adverse events (irAEs) complicate and limit their benefit. IrAEs can affect organ systems idiosyncratically; presentations range from mild and self-limited to fulminant and fatal. The molecular mechanisms underlying irAEs are poorly understood. Here, we report a fatal case of encephalitis arising during anti-programmed cell death receptor 1 therapy in a patient with metastatic melanoma. Histologic analyses revealed robust T cell infiltration and prominent programmed death ligand 1 expression. We identified 209 reported cases in global pharmacovigilance databases (across multiple cancer types) of encephalitis associated with checkpoint inhibitor regimens, with a 19% fatality rate. We performed further analyses from the index case and two additional cases to shed light on this recurrent and fulminant irAE. Spatial and multi-omic analyses pinpointed activated memory CD4 T cells as highly enriched in the inflamed, affected region. We identified a highly oligoclonal T cell receptor repertoire, which we localized to activated memory cytotoxic (CD45ROGZMBKi67) CD4 cells. We also identified Epstein-Barr virus-specific T cell receptors and EBV lymphocytes in the affected region, which we speculate contributed to neural inflammation in the index case. Collectively, the three cases studied here identify CD4 and CD8 T cells as culprits of checkpoint inhibitor-associated immune encephalitis.
0 Communities
1 Members
0 Resources
MeSH Terms
Hypoxia-inducible factors in CD4 T cells promote metabolism, switch cytokine secretion, and T cell help in humoral immunity.
Cho SH, Raybuck AL, Blagih J, Kemboi E, Haase VH, Jones RG, Boothby MR
(2019) Proc Natl Acad Sci U S A 116: 8975-8984
MeSH Terms: Animals, Antibody Formation, B-Lymphocytes, Basic Helix-Loop-Helix Transcription Factors, CD4-Positive T-Lymphocytes, Cell Hypoxia, Cytokines, Germinal Center, Humans, Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit, Immunity, Humoral, Immunization, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Transgenic, Receptors, CXCR5, Sheep, T-Lymphocytes, Helper-Inducer
Show Abstract · Added April 23, 2019
T cell help in humoral immunity includes interactions of B cells with activated extrafollicular CD4 and follicular T helper (Tfh) cells. Each can promote antibody responses but Tfh cells play critical roles during germinal center (GC) reactions. After restimulation of their antigen receptor (TCR) by B cells, helper T cells act on B cells via CD40 ligand and secreted cytokines that guide Ig class switching. Hypoxia is a normal feature of GC, raising questions about molecular mechanisms governing the relationship between hypoxia response mechanisms and T cell help to antibody responses. Hypoxia-inducible factors (HIF) are prominent among mechanisms that mediate cellular responses to limited oxygen but also are induced by lymphocyte activation. We now show that loss of HIF-1α or of both HIF-1α and HIF-2α in CD4 T cells compromised essential functions in help during antibody responses. HIF-1α depletion from CD4 T cells reduced frequencies of antigen-specific GC B cells, Tfh cells, and overall antigen-specific Ab after immunization with sheep red blood cells. Compound deficiency of HIF-1α and HIF-2α led to humoral defects after hapten-carrier immunization. Further, HIF promoted CD40L expression while restraining the FoxP3-positive CD4 cells in the CXCR5 follicular regulatory population. Glycolysis increases T helper cytokine expression, and HIF promoted glycolysis in T helper cells via TCR or cytokine stimulation, as well as their production of cytokines that direct antibody class switching. Indeed, IFN-γ elaboration by HIF-deficient in vivo-generated Tfh cells was impaired. Collectively, the results indicate that HIF transcription factors are vital components of the mechanisms of help during humoral responses.
0 Communities
1 Members
0 Resources
20 MeSH Terms
iNKT Cell Activation Exacerbates the Development of Huntington's Disease in R6/2 Transgenic Mice.
Park HJ, Lee SW, Im W, Kim M, Van Kaer L, Hong S
(2019) Mediators Inflamm 2019: 3540974
MeSH Terms: Animals, Brain, Cytokines, Disease Models, Animal, Disease Progression, Galactosylceramides, Genotype, Huntington Disease, Leukocytes, Lymphocyte Activation, Mice, Mice, Knockout, Natural Killer T-Cells
Show Abstract · Added March 26, 2019
Huntington's disease (HD) is an inherited neurodegenerative disorder which is caused by a mutation of the huntingtin (HTT) gene. Although the pathogenesis of HD has been associated with inflammatory responses, if and how the immune system contributes to the onset of HD is largely unknown. Invariant natural killer T (iNKT) cells are a group of innate-like regulatory T lymphocytes that can rapidly produce various cytokines such as IFN and IL4 upon stimulation with the glycolipid -galactosylceramide (-GalCer). By employing both R6/2 Tg mice (murine HD model) and J18 KO mice (deficient in iNKT cells), we investigated whether alterations of iNKT cells affect the development of HD in R6/2 Tg mice. We found that J18 KO R6/2 Tg mice showed disease progression comparable to R6/2 Tg mice, indicating that the absence of iNKT cells did not have any significant effects on HD development. However, repeated activation of iNKT cells with -GalCer facilitated HD progression in R6/2 Tg mice, and this was associated with increased infiltration of iNKT cells in the brain. Taken together, our results demonstrate that repeated -GalCer treatment of R6/2 Tg mice accelerates HD progression, suggesting that immune activation can affect the severity of HD pathogenesis.
0 Communities
1 Members
0 Resources
13 MeSH Terms
Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism.
Johnson MO, Wolf MM, Madden MZ, Andrejeva G, Sugiura A, Contreras DC, Maseda D, Liberti MV, Paz K, Kishton RJ, Johnson ME, de Cubas AA, Wu P, Li G, Zhang Y, Newcomb DC, Wells AD, Restifo NP, Rathmell WK, Locasale JW, Davila ML, Blazar BR, Rathmell JC
(2018) Cell 175: 1780-1795.e19
MeSH Terms: Animals, CD8-Positive T-Lymphocytes, Cell Differentiation, Glutaminase, Lymphocyte Activation, Male, Mice, Mice, Transgenic, Th1 Cells, Th17 Cells
Show Abstract · Added October 30, 2019
Activated T cells differentiate into functional subsets with distinct metabolic programs. Glutaminase (GLS) converts glutamine to glutamate to support the tricarboxylic acid cycle and redox and epigenetic reactions. Here, we identify a key role for GLS in T cell activation and specification. Though GLS deficiency diminished initial T cell activation and proliferation and impaired differentiation of Th17 cells, loss of GLS also increased Tbet to promote differentiation and effector function of CD4 Th1 and CD8 CTL cells. This was associated with altered chromatin accessibility and gene expression, including decreased PIK3IP1 in Th1 cells that sensitized to IL-2-mediated mTORC1 signaling. In vivo, GLS null T cells failed to drive Th17-inflammatory diseases, and Th1 cells had initially elevated function but exhausted over time. Transient GLS inhibition, however, led to increased Th1 and CTL T cell numbers. Glutamine metabolism thus has distinct roles to promote Th17 but constrain Th1 and CTL effector cell differentiation.
Copyright © 2018 Elsevier Inc. All rights reserved.
0 Communities
2 Members
0 Resources
MeSH Terms
How Superantigens Bind MHC.
Van Kaer L
(2018) J Immunol 201: 1817-1818
MeSH Terms: Animals, Antigens, Bacterial, Clonal Deletion, Enterotoxins, Histocompatibility Antigens, Humans, Lymphocyte Activation, Minor Lymphocyte Stimulatory Antigens, Peptide Fragments, Protein Binding, Receptors, Antigen, T-Cell, alpha-beta, Superantigens, T-Lymphocytes
Added March 26, 2019
0 Communities
1 Members
0 Resources
13 MeSH Terms
NEW STRATEGIES TO PREDICT AND PREVENT SERIOUS IMMUNOLOGICALLY MEDIATED ADVERSE DRUG REACTIONS.
Phillips EJ
(2018) Trans Am Clin Climatol Assoc 129: 74-87
MeSH Terms: Aged, Allopurinol, Animals, Drug Eruptions, Drug Hypersensitivity, Drug-Related Side Effects and Adverse Reactions, Female, Genetic Predisposition to Disease, Gout Suppressants, HLA Antigens, Humans, Lymphocyte Activation, Phenotype, Receptors, Antigen, T-Cell, Risk Assessment, Risk Factors, T-Lymphocytes
Show Abstract · Added March 30, 2020
Preventive efforts for serious immunologically mediated adverse drug reactions (IM-ADRs) have been fueled by discovery of strong class I human leukocyte antigen (HLA) associations; however, the low positive predictive value of HLA for IM-ADRs has limited translation. Studies were undertaken to explain why most patients carrying an HLA risk allele do not develop IM-ADR on exposure to the risk drug. Tissue-specific approaches defined the T-cell receptor (TCR) repertoire and phenotype of the pathogenic T cells found in the skin and blister fluid of IM-ADRs. Dominant CD8+ T cell clonotypes representing >50% of total TCRαβ sequences among CD8+ CD137+ T cells were identified in tissue to identify the pathogenic activated T cells. Identification of the specific molecular and cellular signatures of the antigen-driven pathogenic T cells will facilitate more specific mechanisms to determine the small percentage of individuals carrying an HLA risk allele who are likely to develop an IM-ADR before drug exposure.
0 Communities
1 Members
0 Resources
MeSH Terms
Graphene oxide polarizes iNKT cells for production of TGFβ and attenuates inflammation in an iNKT cell-mediated sepsis model.
Lee SW, Park HJ, Van Kaer L, Hong S, Hong S
(2018) Sci Rep 8: 10081
MeSH Terms: Animals, Antigens, CD1d, Cell Polarity, Dendritic Cells, Disease Models, Animal, Galactosylceramides, Graphite, Humans, Inflammation, Intraepithelial Lymphocytes, Lymphocyte Activation, Mice, Nanotubes, Carbon, Natural Killer T-Cells, Sepsis, Toll-Like Receptor 4, Transforming Growth Factor beta
Show Abstract · Added March 26, 2019
Graphene oxide (GO) modulates the functions of antigen-presenting cells including dendritic cells (DCs). Although carbon nanotubes affect expression of the MHC class I-like CD1d molecule, whether GO can influence immune responses of CD1d-dependent invariant natural killer T (iNKT) cells remains unclear. Here, we investigated the impact of GO on inflammatory responses mediated by α-galactosylceramide (α-GalCer), an iNKT cell agonist. We found that in vivo GO treatment substantially inhibited the capacity of α-GalCer to induce the iNKT cell-mediated trans-activation of and cytokine production by innate and innate-like cells, including DCs, macrophages, NK cells, and γδ T cells. Such effects of GO on α-GalCer-induced inflammatory responses closely correlated with iNKT cell polarization towards TGFβ production, which also explains the capacity of GO to expand regulatory T cells. Interestingly, the absence of TLR4, a receptor for GO, failed to downregulate, and instead partially enhanced the anti-inflammatory activity of GO against α-GalCer-elicited responses, implying negative effects of TLR4 signaling on the anti-inflammatory properties of GO. By employing an α-GalCer-induced sepsis model, we further demonstrated that GO treatment significantly protected mice from α-GalCer-induced lethality. Taken together, we provide strong evidence that GO holds promise as an adjuvant to modulate iNKT cell responses for immunotherapy.
0 Communities
1 Members
0 Resources
17 MeSH Terms
Anti-Insulin B Cells Are Poised for Antigen Presentation in Type 1 Diabetes.
Felton JL, Maseda D, Bonami RH, Hulbert C, Thomas JW
(2018) J Immunol 201: 861-873
MeSH Terms: Animals, Antigen Presentation, Autoantibodies, Autoantigens, B-Lymphocyte Subsets, Diabetes Mellitus, Type 1, Female, Immune Tolerance, Inflammation, Insulin, Insulin Antibodies, Lymphocyte Activation, Male, Mice, Mice, Inbred NOD, Mice, Transgenic, Receptors, Antigen, B-Cell
Show Abstract · Added July 20, 2018
Early breaches in B cell tolerance are central to type 1 diabetes progression in mouse and man. Conventional BCR transgenic mouse models (VH125.Tg NOD) reveal the power of B cell specificity to drive disease as APCs. However, in conventional fixed IgM models, comprehensive assessment of B cell development is limited. To provide more accurate insight into the developmental and functional fates of anti-insulin B cells, we generated a new NOD model (V125NOD) in which anti-insulin VDJH125 is targeted to the IgH chain locus to generate a small (1-2%) population of class switch-competent insulin-binding B cells. Tracking of this rare population in a polyclonal repertoire reveals that anti-insulin B cells are preferentially skewed into marginal zone and late transitional subsets known to have increased sensitivity to proinflammatory signals. Additionally, IL-10 production, characteristic of regulatory B cell subsets, is increased. In contrast to conventional models, class switch-competent anti-insulin B cells proliferate normally in response to mitogenic stimuli but remain functionally silent for insulin autoantibody production. Diabetes development is accelerated, which demonstrates the power of anti-insulin B cells to exacerbate disease without differentiation into Ab-forming or plasma cells. Autoreactive T cell responses in V125NOD mice are not restricted to insulin autoantigens, as evidenced by increased IFN-γ production to a broad array of diabetes-associated epitopes. Together, these results independently validate the pathogenic role of anti-insulin B cells in type 1 diabetes, underscore their diverse developmental fates, and demonstrate the pathologic potential of coupling a critical β cell specificity to predominantly proinflammatory Ag-presenting B cell subsets.
Copyright © 2018 by The American Association of Immunologists, Inc.
1 Communities
1 Members
0 Resources
17 MeSH Terms