A5058890692- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Monoclonal and Polyclonal Antibodies Research
- Immunotherapy and Immune Responses
- Congenital heart defects research
- CAR-T cell therapy research
- MicroRNA in disease regulation
- Cytokine Signaling Pathways and Interactions
- RNA modifications and cancer
- Cancer-related molecular mechanisms research
- Mycobacterium research and diagnosis
- Galectins and Cancer Biology
- Congenital Heart Disease Studies
- Tuberculosis Research and Epidemiology
- Signaling Pathways in Disease
- RNA and protein synthesis mechanisms
- Ubiquitin and proteasome pathways
- Immune Response and Inflammation
- Cancer Immunotherapy and Biomarkers
- Systemic Lupus Erythematosus Research
- Immunodeficiency and Autoimmune Disorders
- Protein Tyrosine Phosphatases
- Circular RNAs in diseases
- NF-κB Signaling Pathways
- Cell Adhesion Molecules Research
The University of Texas Southwestern Medical Center
2015-2025
Southwestern Medical Center
2008-2025
Pediatrics and Genetics
2013-2022
University of Toledo
2014
Institute of Molecular Biology and Biophysics
2013
Institute of Neuroimmunology of the Slovak Academy of Sciences
2009
Columbia University
2008
Institute of Immunology
2003-2005
Howard Hughes Medical Institute
1994-2000
Bipar
1999
The T cell antigen receptor (TCR) initiates signals by interacting with cytoplasmic protein tyrosine kinases (PTKs) through a 17-residue sequence motif [called the recognition activation (ARAM)] that is contained in TCRζ and CD3 chains. TCR stimulation induces phosphorylation of several cellular substrates, including ARAMs. Lck kinase activity required for two conserved residues an ARAM. This leads to recruitment second PTK, ZAP-70, both ZAP-70 Src homology 2 domains its phosphorylation....
The Src-family and Syk/ZAP-70 family of protein tyrosine kinases (PTK) are required for T cell receptor (TCR) functions. We provide evidence that the PTK Lck is responsible regulating constitutive phosphorylation TCR zeta subunit in murine thymocytes. Moreover, ligation expressed on thymocytes from Lck-deficient mice largely failed to induce TCR-zeta, CD3 epsilon, or ZAP-70. In contrast, we find TCR-zeta weakly constitutively phosphorylated peripheral cells isolated Lck-null mice. These data...
Abstract TCR stimulation results in the tyrosine phosphorylation of a number cellular substrates. We have recently identified 70-kDa protein kinase, ZAP-70, which associates with human zeta-chain after stimulation. report here isolation and sequence cDNA clone that encodes murine ZAP-70. Murine ZAP-70 share 93% amino acid identity are homologous to 72-kDa kinase Syk. Syk has been implicated signal transduction pathways B cell membrane Ig high affinity IgE receptors, Fc epsilon RI. In...
We hypothesize that low-level efflux pump expression is the first step in development of high-level drug resistance mycobacteria. performed 28-day azithromycin dose-effect and dose-scheduling studies our hollow-fiber model disseminated Mycobacterium avium-M. intracellulare complex. Both microbial kill emergence were most closely linked to within-macrophage area under concentration-time curve (AUC)/MIC ratio. Quantitative PCR revealed subtherapeutic exposures over 3 days led a 56-fold...
The Src family protein tyrosine kinases (PTKs), Lck and Fyn, are coexpressed in T cells perform crucial functions involved the initiation of cell antigen receptor (TCR) signal transduction. However, mechanisms by which Fyn regulate TCR signaling still not completely understood. One important question is whether have specific targets or only provide functional redundancy during signaling. We previously shown that plays a major role phosphorylation TCR-ζ chain ZAP-70 PTK. In an effort to...
A system that allows the study, in a gentle fashion, of role MHC molecules naive T cell survival is described. Major histocompatibility complex class II–deficient mice were engineered to express Eα chains only thymic epithelial cells tetracycline (tet)-controllable manner. This resulted tet-responsive display surface E complexes, positive selection CD4+8– thymocytes, and generation CD4+ compartment II–barren periphery. Using this system, we have addressed two unresolved issues: half-life...
Abstract T cell activation involves a cascade of TCR-mediated signals that are regulated by three distinct intracellular signaling motifs located within the cytoplasmic tails CD3 chains. Whereas all subunits possess at least one ITAM, ε subunit also contains proline-rich sequence and basic-rich stretch (BRS). The BRS complexes selected phosphoinositides, interactions required for normal surface expression TCR. domain ζ several clusters arginine lysine residues. In this study, we report these...
Germline coding mutations in different telomere-related genes have been linked to autosomal-dominant familial pulmonary fibrosis. Individuals with these inherited demonstrate incomplete penetrance of clinical phenotypes affecting the lung, blood, liver, skin, and other organs. Here, we describe somatic acquisition promoter telomerase reverse transcriptase (TERT) blood leukocytes approximately 5% individuals loss-of-function TERT or poly(A)-specific ribonuclease (PARN), another gene function....
The Syk/ZAP-70 family of protein tyrosine kinases is indispensable for normal lymphoid development. Syk necessary the development B cells and epithelial gammadelta T cells, whereas ZAP-70 essential TCR signaling. In this study, we show that although alphabeta lineage was arrested in thymus, CD3-positive primarily lineage, were present lymph nodes mice lacking ZAP-70. Moreover, absence ZAP-70, dendritic epidermal fewer number abnormal morphology, intestinal intraepithelial lymphocytes,...
During T cell activation, receptors (TCR) cluster at the center of cell/antigen-presenting interface forming a key component immunological synapse. The function this TCR clustering is still unresolved. A comprehensive search for such yielded very limited and specific result. micrometer-scale receptor integrated CD28 signals required IL-2 secretion in primary 5C.C7 cells, low-affinity/avidity system. signaling itself was not affected. In addition, central accumulation any effector tested...
The pre-T cell receptor (TCR) complex regulates early T development and consists of a heterodimer the TCR-beta subunit in association with pre-TCR-alpha chain. Notably, contrast to alpha/beta-expressing cells, several studies suggested that TCR-zeta chain is not stably associated this pre-TCR complex. To examine proximal signaling processes mediated by role these processes, we stimulated pre-TCR-expressing cells analyzed interactions TCR/CD3 invariant chains Syk/ZAP-70 family protein...
The timing and the distribution of signaling intermediates reflect efficiency nature T cell receptor activation.
The CD3 epsilon subunit of the TCR complex contains two defined signaling domains, a proline-rich sequence and an ITAM. We identified third in epsilon, termed basic-rich stretch (BRS). Herein, we show that positively charged residues BRS enable this region to subset acidic phospholipids, including PI(3)P, PI(4)P, PI(5)P, PI(3,4,5)P(3), PI(4,5)P(2). Transgenic mice containing mutations exhibited varying developmental defects, ranging from reduced thymic cellularity complete block T cell...
Bead-beating within a DNA extraction protocol is critical for complete microbial cell lysis and accurate assessment of the abundance composition microbiome. While impact bead-beating on recovery OTUs at phylum class level have been studied, its influence species-level microbiome not clear. Recent advances in sequencing technology has allowed resolution using full length 16S rRNA gene instead smaller amplicons that only capture few hypervariable regions gene. We sequenced v3-v4 region as well...
An accurate diagnosis of septic versus reactive or autoimmune arthritis remains clinically challenging. A multi-omics strategy comprising metagenomic and proteomic technologies were undertaken for children diagnosed with presumed to advance clinical diagnoses care affected individuals. Twelve suspected prospectively enrolled compare standard tests a rapid approach. The combined bacterial 16S rRNA metagenomics, single cell transcriptomics, proteomics on knee joint fluid specimens. diagnostic...
This collaborative study, led by the Clinical Genome Resource Severe Combined Immunodeficiency Disease Variant Curation Expert Panel (ClinGen SCID-VCEP), implemented and adapted American College of Medical Genetics Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines interpreting germline variants in genes with established relationships to SCID. The effort focused on 7 most common SCID-related identified SCID newborn screening North America: ADA , DCLRE1C IL2RG IL7R JAK3 RAG1...
The T-cell receptor (TCR) zeta subunit is an important component of the TCR complex, involved in signal transduction events following engagement. In this study, we showed that chain constitutively tyrosine phosphorylated to similar extents thymocytes and lymph node T cells. Approximately 35% tyrosine-phosphorylated (phospho zeta) precipitated from total cell lysates appeared be surface associated. Furthermore, constitutive phosphorylation cells occurred independently antigen stimulation did...