John E. Bradley
University of Alabama at Birmingham
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Featured researches published by John E. Bradley.
Nature Communications | 2014
Beatriz León; John E. Bradley; Frances E. Lund; Troy D. Randall; André Ballesteros-Tato
Summary Here we test the role of FoxP3+ regulatory T cells (Tregs) in controlling T follicular helper (Tfh) and germinal-center (GC) B cell responses to influenza. In contrast to the idea that Tregs suppress T cell responses, we find that Treg depletion severely reduces the Tfh cell response to influenza virus. Furthermore, Treg depletion prevents the accumulation of influenza-specific GCs. These effects are not due to alterations in TGFβ availability or a precursor-progeny relationship between Tregs and Tfh cells, but are instead mediated by increased availability of IL-2, which suppresses the differentiation of Tfh cells and as a consequence, compromises the GC B response. Thus, Tregs promote influenza-specific GC responses by preventing excessive IL-2 signaling, which suppresses Tfh cell differentiation.
Biofactors | 2009
John E. Bradley; Gustavo Ramírez; James S. Hagood
Thy‐1 or CD90 is a glycophosphatidylinositol‐linked glycoprotein expressed on the surface of neurons, thymocytes, subsets of fibroblasts, endothelial cells, mesangial cells and some hematopoietic cells. Thy‐1 is evolutionarily conserved, developmentally regulated, and often has dramatic effects on cell phenotype; however, the effects vary between and in some cases within cell types and tissues, and between similar tissues in different species, indicating that the biological role of Thy‐1 is context‐dependent. Thy‐1 exists in soluble form in some body fluids; however, the mechanisms of its shedding are unknown. In addition, Thy‐1 expression can be regulated by epigenetic silencing. Because Thy‐1 modulates many basic cellular processes and is involved in the pathogenesis of a number of diseases, it is important to better understand its regulation.
Nature Immunology | 2017
Davide Botta; Michael J. Fuller; Tatiana T. Marquez-Lago; Holly Bachus; John E. Bradley; Amy S. Weinmann; Allan J. Zajac; Troy D. Randall; Frances E. Lund; Beatriz León; André Ballesteros-Tato
Interleukin 2 (IL-2) promotes Foxp3+ regulatory T (Treg) cell responses, but inhibits T follicular helper (TFH) cell development. However, it is not clear how IL-2 affects T follicular regulatory (TFR) cells, a cell type with properties of both Treg and TFH cells. Using an influenza infection model, we found that high IL-2 concentrations at the peak of the infection prevented TFR cell development by a Blimp-1-dependent mechanism. However, once the immune response resolved, some Treg cells downregulated CD25, upregulated Bcl-6 and differentiated into TFR cells, which then migrated into the B cell follicles to prevent the expansion of self-reactive B cell clones. Thus, unlike its effects on conventional Treg cells, IL-2 inhibits TFR cell responses.
Journal of Immunology | 2015
Jennie A. Hamilton; Jun Li; Qi Wu; PingAr Yang; Bao Luo; Hao Li; John E. Bradley; Justin J. Taylor; Troy D. Randall; John D. Mountz; Hui-Chen Hsu
Autoreactive B cells are associated with the development of several autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis. The low frequency of these cells represents a major barrier to their analysis. Ag tetramers prepared from linear epitopes represent a promising strategy for the identification of small subsets of Ag-reactive immune cells. This is challenging given the requirement for identification and validation of linear epitopes and the complexity of autoantibody responses, including the broad spectrum of autoantibody specificities and the contribution of isotype to pathogenicity. Therefore, we tested a two-tiered peptide microarray approach, coupled with epitope mapping of known autoantigens, to identify and characterize autoepitopes using the BXD2 autoimmune mouse model. Microarray results were verified through comparison with established age-associated profiles of autoantigen specificities and autoantibody class switching in BXD2 and control (C57BL/6) mice and high-throughput ELISA and ELISPOT analyses of synthetic peptides. Tetramers were prepared from two linear peptides derived from two RNA-binding proteins (RBPs): lupus La and 70-kDa U1 small nuclear ribonucleoprotein. Flow cytometric analysis of tetramer-reactive B cell subsets revealed a significantly higher frequency and greater numbers of RBP-reactive marginal zone precursor, transitional T3, and PDL-2+CD80+ memory B cells, with significantly elevated CD69 and CD86 observed in RBP+ marginal zone precursor B cells in the spleens of BXD2 mice compared with C57BL/6 mice, suggesting a regulatory defect. This study establishes a feasible strategy for the characterization of autoantigen-specific B cell subsets in different models of autoimmunity and, potentially, in humans.
Laboratory Investigation | 2013
John E. Bradley; Joy M. Chan; James S. Hagood
Thymocyte differentiation antigen-1 (Thy-1) is a glycosylphosphatidylinositol (GPI)-linked cell surface glycoprotein expressed on numerous cell types, which regulates signals affecting cell adhesion, migration, differentiation, and survival. In addition, Thy-1 has been detected in the serum, cerebral spinal fluid, wound fluid from venous ulcers, synovial fluid from joints in rheumatoid arthritis, and, more recently, urine. We previously detected Thy-1 in the conditioned media of cytokine-stimulated lung fibroblasts, suggesting that Thy-1 shedding may be a response to cellular stress. Soluble and membrane-bound forms of Thy-1 from in vivo sources have been shown to be identical in size when deglycosylated, suggesting that soluble Thy-1 is separated from the diacyl glycerol portion of its GPI anchor by hydrolysis within the GPI moiety. For Thy-1- and other GPI-anchored proteins, delipidation induces a stable change in conformation that manifests itself in a change in antibody affinity for soluble forms. Using epitope-tagged recombinant soluble Thy-1, we report that widely available monoclonal antibodies to human Thy-1 are unable to detect soluble Thy-1 by immunoblotting. We re-evaluated the Thy-1 that we previously reported in the conditioned media of normal human lung fibroblasts and found it to be entirely insoluble. These findings suggest that most Thy-1 reported in body fluids retains its GPI anchor and may be associated with membrane fragments or vesicles. This phenomenon should be considered in the generation of antibodies and controls for Thy-1 bioassays. Furthermore, the changes in Thy-1 conformation with delipidation, beyond affecting antibody affinity, likely affect the ligand affinity and biological function of soluble vs released membrane-associated forms.
Journal of Immunology | 2018
Muyao Guo; Madeline J. Price; Dillon G. Patterson; Benjamin G. Barwick; Robert R. Haines; Anna K. Kania; John E. Bradley; Troy D. Randall; Jeremy M. Boss; Christopher D. Scharer
Epigenetic remodeling is required during B cell differentiation. However, little is known about the direct functions of epigenetic enzymes in Ab-secreting cells (ASC) in vivo. In this study, we examined ASC differentiation independent of T cell help and germinal center reactions using mice with inducible or B cell–specific deletions of Ezh2. Following stimulation with influenza virus or LPS, Ezh2-deficient ASC poorly proliferated and inappropriately maintained expression of inflammatory pathways, B cell–lineage transcription factors, and Blimp-1–repressed genes, leading to fewer and less functional ASC. In the absence of EZH2, genes that normally gained histone H3 lysine 27 trimethylation were dysregulated and exhibited increased chromatin accessibility. Furthermore, EZH2 was also required for maximal Ab secretion by ASC, in part due to reduced mitochondrial respiration, impaired glucose metabolism, and poor expression of the unfolded-protein response pathway. Together, these data demonstrate that EZH2 is essential in facilitating epigenetic changes that regulate ASC fate, function, and metabolism.
Laboratory Investigation | 2017
Xiaoqiu Liu; Simon S. Wong; Carmen A. Taype; Jeeyeon Kim; Tzu-Pin Shentu; Celia Espinoza; J. Cameron Finley; John E. Bradley; Brian P. Head; Hemal H. Patel; Emma J. Mah; James S. Hagood
Thy-1-negative lung fibroblasts are resistant to apoptosis. The mechanisms governing this process and its relevance to fibrotic remodeling remain poorly understood. By using either sorted or transfected lung fibroblasts, we found that Thy-1 expression is associated with downregulation of anti-apoptotic molecules Bcl-2 and Bcl-xL, as well as increased levels of cleaved caspase-9. Addition of rhFasL and staurosporine, well-known apoptosis inducers, caused significantly increased cleaved caspase-3, -8, and PARP in Thy-1-transfected cells. Furthermore, rhFasL induced Fas translocation into lipid rafts and its colocalization with Thy-1. These in vitro results indicate that Thy-1, in a manner dependent upon its glycophosphatidylinositol anchor and lipid raft localization, regulates apoptosis in lung fibroblasts via Fas-, Bcl-, and caspase-dependent pathways. In vivo, Thy-1 deficient (Thy1−/−) mice displayed persistence of myofibroblasts in the resolution phase of bleomycin-induced fibrosis, associated with accumulation of collagen and failure of lung fibrosis resolution. Apoptosis of myofibroblasts is decreased in Thy1−/− mice in the resolution phase. Collectively, these findings provide new evidence regarding the role and mechanisms of Thy-1 in initiating myofibroblast apoptosis that heralds the termination of the reparative response to bleomycin-induced lung injury. Understanding the mechanisms regulating fibroblast survival/apoptosis should lead to novel therapeutic interventions for lung fibrosis.
Investigative Ophthalmology & Visual Science | 2013
Nicole Guyette; Larezia Williams; My-Tho Tran; Tammy Than; John E. Bradley; L. E. Kehinde; Clara S. Edwards; Mark Beasley; Roderick J. Fullard
Investigative Ophthalmology & Visual Science | 2011
Tammy Than; Nicole Guyette; Karin Tran; Keshia S. Elder; Janene Sims; L. E. Kehinde; Pearl Shin; Larezia Williams; John E. Bradley; Roderick J. Fullard
Journal of Immunology | 2015
Jennie A. Hamilton; Jun Li; Qi Wu; PingAr Yang; Bao Luo; Hao Li; John E. Bradley; Justin J. Taylor; Troy D. Randall; John D. Mountz; Hui-Chen Hsu