A5072221107- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- CAR-T cell therapy research
- Acute Lymphoblastic Leukemia research
- Immunotherapy and Immune Responses
- interferon and immune responses
- Immune responses and vaccinations
- Epigenetics and DNA Methylation
- Chronic Lymphocytic Leukemia Research
- SARS-CoV-2 and COVID-19 Research
- Lymphoma Diagnosis and Treatment
- Computational Geometry and Mesh Generation
- Advanced Graph Theory Research
- Atherosclerosis and Cardiovascular Diseases
- Immunodeficiency and Autoimmune Disorders
- Cancer-related molecular mechanisms research
- Cytokine Signaling Pathways and Interactions
- DNA and Nucleic Acid Chemistry
- RNA Interference and Gene Delivery
- Galectins and Cancer Biology
- Whipple's Disease and Interleukins
- Systemic Lupus Erythematosus Research
- Genetic Associations and Epidemiology
- Geometric and Algebraic Topology
- Genomics and Chromatin Dynamics
Children's Hospital of Philadelphia
2009-2024
University of Pennsylvania
2006-2024
Institute for Stem Cell Biology and Regenerative Medicine
2023
Philadelphia University
2006
Kaplan (United States)
2001-2003
New York University
2001-2003
Environmental and Occupational Health Sciences Institute
1999
Josai University
1999
Rutgers, The State University of New Jersey
1993-1995
Georgia Institute of Technology
1993-1995
Regulatory T cells (T(reg)) express Foxp3, a forkhead family member that is necessary and sufficient for T(reg) lineage choice function. Ectopic expression of Foxp3 in non-T(reg) leads to repression the interleukin 2 (IL-2) interferon gamma (IFNgamma) genes, gain suppressor function, induction genes such as CD25, GITR, CTLA-4, but mode by which enforces this program unclear. Using chromatin immunoprecipitation, we have demonstrated binds endogenous IL-2 IFNgamma loci cells, only after cell...
Abstract Memory T cells (TM) are able to rapidly exert effector functions, including immediate cytokine production upon re-encounter with Ag, which is critical for protective immunity. Furthermore, this poised state maintained as TM undergo homeostatic proliferation over time. We examined the molecular basis underlying enhanced functional capacity in CD8 by comparing them defective generated absence of CD4 cells. Unhelped many expression cytokines, such IL-2 and IFN-γ. Our data show that...
Abstract Systemic lupus erythematosus (SLE) is mediated by autoreactive antibodies that damage multiple tissues. Genome-wide association studies (GWAS) link >60 loci with SLE risk, but the causal variants and effector genes are largely unknown. We generated high-resolution spatial maps of variant accessibility gene connectivity in human follicular helper T cells (TFH), a cell type required for anti-nuclear characteristic SLE. Of ~400 potential regulatory identified, 90% exhibit proximity...
Abstract CD28 costimulation controls multiple aspects of T cell function, including the expression proinflammatory cytokine genes. One these genes encodes IL-2, a growth factor that influences proliferation, survival, and differentiation. Antigenic signaling in absence leads to anergy, mechanism tolerance renders CD4+ cells unable produce IL-2. The molecular mechanisms by which costimulatory signals induce gene are not fully understood. In eukaryotic cells, many is influenced their physical...
Use of Foxp3-positive (Foxp3(+)) T-regulatory (Treg) cells as potential cellular therapy in patients with autoimmunity, or post-stem cell -organ transplantation, requires a sound understanding the transcriptional regulation Foxp3. Conserved CpG dinucleotides Treg-specific demethylation region (TSDR) upstream Foxp3 are demethylated only stable, thymus-derived Foxp3(+) Treg cells. Since methyl-binding domain (Mbd) proteins recruit histone-modifying and chromatin-remodeling complexes to...
Naïve CD4+ T cells are highly plastic and can differentiate into discrete lineages with unique functions during an immune response. Once differentiated, helper maintain a stable transcriptional memory of their initial lineage choice resist redifferentiation. During embryogenesis, de novo DNA methylation operates on the hypomethylated genome blastocyst to achieve tissue-specific patterns gene expression. Similarly, ifnγ promoter is in naïve cells, but Th2, Th17, iTreg differentiation...
Abstract Background SARS-CoV-2 infection results in a broad spectrum of COVID-19 disease, from mild or no symptoms to hospitalization and death. disease severity has been associated with some pre-existing conditions the magnitude adaptive immune response SARS-CoV-2, recent genome-wide association study (GWAS) risk critical illness revealed significant genetic component. To gain insight into how human variation attenuates exacerbates following infection, we implicated putatively functional...
Abstract T cell activation results in dynamic remodeling of the chromatin at IL2 promoter and induction gene transcription. These processes are each dependent upon CD28 costimulation, but molecular basis for this requirement is not clear. The contains consensus-binding elements Ikaros, a lymphocyte-specific zinc-finger DNA-binding protein that can regulate expression by recruiting chromatin-remodeling complexes. We find native Ikaros CD4+ cells exhibits sequence-specific binding to these...
Background: IL-17 is an inflammatory cytokine that mediates immunopathology in autoimmune disease.Results: DNA methylation at the il17 locus lineage-restricted and blocks STAT3 binding.Conclusion: Expression of genes regulated by promoter a novel intergenic enhancer.Significance: Understanding mechanisms regulating production will facilitate therapeutic control immune responses. disease. Results: binding. Conclusion: enhancer. Significance:
Abstract Naturally occurring CD4+CD25+ regulatory T cells (Tregs), which play an important role in the maintenance of self-tolerance, proliferate poorly and fail to produce IL-2 following stimulation vitro with peptide-pulsed or anti-CD3-treated APCs. When TCR proximal distal signaling events were examined Tregs, we observed impairments amplitude duration tyrosine phosphorylation when compared response CD4+CD25− cells. Defects also seen activity phospholipase C-γ signals downstream this...
CD4+ T cells can be instructed by nonantigen-specific signals to differentiate into functionally distinct lineages with mutually exclusive patterns of cytokine production. The molecular events that drive interferon-gamma (IFN gamma) production during Th1 development are well understood, but mechanisms silence this Th2 polarization not clear. In study, we find the tbx21 gene encoding master regulator T-bet is a direct target transcriptional repressor Ikaros. cells, which do express T-bet,...
Naive CD4(+) T cells require signals from the TCR and CD28 to produce IL-2, expand, differentiate. However, these same are not sufficient induce autocrine IL-2 production by naive CD8(+) cells, which cytokines provided other cell types drive their differentiation. The basis for failed activated is unclear. We find that Ikaros, a transcriptional repressor silences in anergic also restricts cells. activation vitro absence of exogenous CD4 help leads marked induction known Il2 gene. murine CD8...
Abstract Foxp3 + T regulatory (T reg ) cells suppress immune cell activation and establish normal homeostasis. How maintain their identity is not completely understood. Here we show that Ndfip1, a coactivator of Nedd4-family E3 ubiquitin ligases, required for stability function. Ndfip1 deletion in results autoinflammatory disease. Ndfip1-deficient are highly proliferative more likely to lose expression become IL-4-producing H 2 effector cells. Proteomic analyses indicate altered metabolic...
Genome-wide association studies (GWAS) have identified hundreds of genetic signals associated with autoimmune disease. The majority these are located in non-coding regions and likely impact cis -regulatory elements (cRE). Because cRE function is dynamic across cell types states, profiling the epigenetic status physiological processes necessary to characterize molecular mechanisms by which variants contribute disease risk. We localized risk from 15 GWAS active during TCR-CD28 co-stimulation...
Abstract Although T cells infiltrate many types of murine and human neoplasms, in instances tumor-specific cytotoxicity is not observed. Strategies to stimulate CTL-mediated antitumor immunity have included vitro stimulation and/or genetic engineering cells, followed by adoptive transfer into tumor-bearing hosts. In this model B cell lymphoma SJL/J mice, we used Tim-3+ T-bet+ Th1 facilitate the development CTL. Tumor-specific lines were polarized with IL-12 during long term maintenance. As...
Ikaros is a transcriptional factor required for conventional T cell development, differentiation, and anergy. While the related factors Helios Eos have defined roles in regulatory cells (Treg), role has not been established. To determine function of Treg lineage, we generated mice with Treg-specific deletion gene ( Ikzf1 ). We find that cooperates Foxp3 to establish major portion epigenome transcriptome. Ikaros-deficient exhibit Th1-like expression abnormal production IL-2, IFNg, TNFa,...
ABSTRACT A portion of the genetic basis for many common autoimmune disorders has been uncovered by genome-wide association studies (GWAS), but GWAS do not reveal causal variants, effector genes, or cell types impacted disease-associated variation. We have generated 3D genomic datasets consisting promoter-focused Capture-C, Hi-C, ATAC-seq, and RNA-seq integrated these data with 16 traits to physically map variants genes they likely regulate in 57 human types. These maps gene cis -regulatory...
The inefficient uptake of oligodeoxynucleotides, including that TFO, through the cell membrane is a limiting factor in developing gene therapy approaches for cancer and other diseases. To develop new strategy oligonucleotide delivery into nucleus, we synthesized series novel polyamine analogues examined their effects on 37-mer [32P]-labeled targeted to promoter region c-myc oncogene. We used MCF-7 breast cells investigate efficacy polyamines internalization TFO. TFO was enhanced by...
Abstract Spontaneous germinal center (GC)-derived B cell lymphomas of SJL mice (RCS) transcribe a 1.8-kb Mtv-29 mRNA under control the META-env promoter. The encoded vSAg29 stimulates syngeneic Vβ16+ CD4+ T cells, thereby acquiring help necessary for RCS growth. Other strains lymphoma-prone include Mtv29+ C57L and MA/MyJ, Mtv29− Mtv7+-recombinant inbred strain, SW × J-1. these produce similar mouse mtv-vSAg-encoding mRNA, as characterized by Northern blotting, PCR, RNase protection. A in...