Publications by authors named "Jonathan Kaye"

72 Publications

Persistence of self-reactive CD8+ T cells in the CNS requires TOX-dependent chromatin remodeling.

Nat Commun 2021 02 12;12(1):1009. Epub 2021 Feb 12.

Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.

Self-reactive CD8 T cells are important mediators of progressive tissue damage in autoimmune diseases, but the molecular program underlying these cells' functional adaptation is unclear. Here we characterize the transcriptional and epigenetic landscape of self-reactive CD8 T cells in a mouse model of protracted central nervous system (CNS) autoimmunity and compare it to populations of CNS-resident memory CD8 T cells emerging from acute viral infection. We find that autoimmune CD8 T cells persisting at sites of self-antigen exhibit characteristic transcriptional regulation together with distinct epigenetic remodeling. This self-reactive CD8 T cell fate depends on the transcriptional regulation by the DNA-binding HMG-box protein TOX which remodels more than 400 genomic regions including loci such as Tcf7, which is central to stemness of CD8 T cells. Continuous exposure to CNS self-antigen sustains TOX levels in self-reactive CD8 T cells, whereas genetic ablation of TOX in CD8 T cells results in shortened persistence of self-reactive CD8 T cells in the inflamed CNS. Our study establishes and characterizes the genetic differentiation program enabling chronic T cell-driven immunopathology in CNS autoimmunity.
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http://dx.doi.org/10.1038/s41467-021-21109-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881115PMC
February 2021

Inhibition of the CCL2 receptor, CCR2, enhances tumor response to immune checkpoint therapy.

Commun Biol 2020 Nov 27;3(1):720. Epub 2020 Nov 27.

Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA.

Immunotherapies targeting the PD-1/PD-L1 axis are now a mainstay in the clinical management of multiple cancer types, however, many tumors still fail to respond. CCL2 is highly expressed in various cancer types and has been shown to be associated with poor prognosis. Inhibition or blockade of the CCL2/CCR2 signaling axis has thus been an area of interest for cancer therapy. Here we show across multiple murine tumor and metastasis models that CCR2 antagonism in combination with anti-PD-1 therapy leads to sensitization and enhanced tumor response over anti-PD-1 monotherapy. We show that enhanced treatment response correlates with enhanced CD8 T cell recruitment and activation and a concomitant decrease in CD4 regulatory T cell. These results provide strong preclinical rationale for further clinical exploration of combining CCR2 antagonism with PD-1/PD-L1-directed immunotherapies across multiple tumor types especially given the availability of small molecule CCR2 inhibitors and antibodies.
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http://dx.doi.org/10.1038/s42003-020-01441-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699641PMC
November 2020

Publisher Correction: Genetic tool development in marine protists: emerging model organisms for experimental cell biology.

Authors:
Drahomíra Faktorová R Ellen R Nisbet José A Fernández Robledo Elena Casacuberta Lisa Sudek Andrew E Allen Manuel Ares Cristina Aresté Cecilia Balestreri Adrian C Barbrook Patrick Beardslee Sara Bender David S Booth François-Yves Bouget Chris Bowler Susana A Breglia Colin Brownlee Gertraud Burger Heriberto Cerutti Rachele Cesaroni Miguel A Chiurillo Thomas Clemente Duncan B Coles Jackie L Collier Elizabeth C Cooney Kathryn Coyne Roberto Docampo Christopher L Dupont Virginia Edgcomb Elin Einarsson Pía A Elustondo Fernan Federici Veronica Freire-Beneitez Nastasia J Freyria Kodai Fukuda Paulo A García Peter R Girguis Fatma Gomaa Sebastian G Gornik Jian Guo Vladimír Hampl Yutaka Hanawa Esteban R Haro-Contreras Elisabeth Hehenberger Andrea Highfield Yoshihisa Hirakawa Amanda Hopes Christopher J Howe Ian Hu Jorge Ibañez Nicholas A T Irwin Yuu Ishii Natalia Ewa Janowicz Adam C Jones Ambar Kachale Konomi Fujimura-Kamada Binnypreet Kaur Jonathan Z Kaye Eleanna Kazana Patrick J Keeling Nicole King Lawrence A Klobutcher Noelia Lander Imen Lassadi Zhuhong Li Senjie Lin Jean-Claude Lozano Fulei Luan Shinichiro Maruyama Tamara Matute Cristina Miceli Jun Minagawa Mark Moosburner Sebastián R Najle Deepak Nanjappa Isabel C Nimmo Luke Noble Anna M G Novák Vanclová Mariusz Nowacki Isaac Nuñez Arnab Pain Angela Piersanti Sandra Pucciarelli Jan Pyrih Joshua S Rest Mariana Rius Deborah Robertson Albane Ruaud Iñaki Ruiz-Trillo Monika A Sigg Pamela A Silver Claudio H Slamovits G Jason Smith Brittany N Sprecher Rowena Stern Estienne C Swart Anastasios D Tsaousis Lev Tsypin Aaron Turkewitz Jernej Turnšek Matus Valach Valérie Vergé Peter von Dassow Tobias von der Haar Ross F Waller Lu Wang Xiaoxue Wen Glen Wheeler April Woods Huan Zhang Thomas Mock Alexandra Z Worden Julius Lukeš

Nat Methods 2020 05;17(5):551

Institute of Parasitology, Biology Centre, Czech Academy of Sciences and Faculty of Sciences, University of South Bohemia, České Budějovice, Czech Republic.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41592-020-0828-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200595PMC
May 2020

Genetic tool development in marine protists: emerging model organisms for experimental cell biology.

Authors:
Drahomíra Faktorová R Ellen R Nisbet José A Fernández Robledo Elena Casacuberta Lisa Sudek Andrew E Allen Manuel Ares Cristina Aresté Cecilia Balestreri Adrian C Barbrook Patrick Beardslee Sara Bender David S Booth François-Yves Bouget Chris Bowler Susana A Breglia Colin Brownlee Gertraud Burger Heriberto Cerutti Rachele Cesaroni Miguel A Chiurillo Thomas Clemente Duncan B Coles Jackie L Collier Elizabeth C Cooney Kathryn Coyne Roberto Docampo Christopher L Dupont Virginia Edgcomb Elin Einarsson Pía A Elustondo Fernan Federici Veronica Freire-Beneitez Nastasia J Freyria Kodai Fukuda Paulo A García Peter R Girguis Fatma Gomaa Sebastian G Gornik Jian Guo Vladimír Hampl Yutaka Hanawa Esteban R Haro-Contreras Elisabeth Hehenberger Andrea Highfield Yoshihisa Hirakawa Amanda Hopes Christopher J Howe Ian Hu Jorge Ibañez Nicholas A T Irwin Yuu Ishii Natalia Ewa Janowicz Adam C Jones Ambar Kachale Konomi Fujimura-Kamada Binnypreet Kaur Jonathan Z Kaye Eleanna Kazana Patrick J Keeling Nicole King Lawrence A Klobutcher Noelia Lander Imen Lassadi Zhuhong Li Senjie Lin Jean-Claude Lozano Fulei Luan Shinichiro Maruyama Tamara Matute Cristina Miceli Jun Minagawa Mark Moosburner Sebastián R Najle Deepak Nanjappa Isabel C Nimmo Luke Noble Anna M G Novák Vanclová Mariusz Nowacki Isaac Nuñez Arnab Pain Angela Piersanti Sandra Pucciarelli Jan Pyrih Joshua S Rest Mariana Rius Deborah Robertson Albane Ruaud Iñaki Ruiz-Trillo Monika A Sigg Pamela A Silver Claudio H Slamovits G Jason Smith Brittany N Sprecher Rowena Stern Estienne C Swart Anastasios D Tsaousis Lev Tsypin Aaron Turkewitz Jernej Turnšek Matus Valach Valérie Vergé Peter von Dassow Tobias von der Haar Ross F Waller Lu Wang Xiaoxue Wen Glen Wheeler April Woods Huan Zhang Thomas Mock Alexandra Z Worden Julius Lukeš

Nat Methods 2020 05 6;17(5):481-494. Epub 2020 Apr 6.

Institute of Parasitology, Biology Centre, Czech Academy of Sciences and Faculty of Sciences, University of South Bohemia, České Budějovice, Czech Republic.

Diverse microbial ecosystems underpin life in the sea. Among these microbes are many unicellular eukaryotes that span the diversity of the eukaryotic tree of life. However, genetic tractability has been limited to a few species, which do not represent eukaryotic diversity or environmentally relevant taxa. Here, we report on the development of genetic tools in a range of protists primarily from marine environments. We present evidence for foreign DNA delivery and expression in 13 species never before transformed and for advancement of tools for eight other species, as well as potential reasons for why transformation of yet another 17 species tested was not achieved. Our resource in genetic manipulation will provide insights into the ancestral eukaryotic lifeforms, general eukaryote cell biology, protein diversification and the evolution of cellular pathways.
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http://dx.doi.org/10.1038/s41592-020-0796-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200600PMC
May 2020

Describing the dynamic translational science landscape through Core Voucher utilization.

J Clin Transl Sci 2019 Jun 14;3(2-3):105-112. Epub 2019 Jun 14.

Division of Hematology/Oncology, Department of Pediatrics, Gwynne Hazen Cherry Memorial Laboratories, University of California, Los Angeles, CA, USA.

Introduction: Core facilities play crucial roles in carrying out the academic research mission by making available to researchers advanced technologies, facilities, or expertise that are unfeasible for most investigators to obtain on their own. To facilitate translational science through support of core services, the University of California, Los Angeles Clinical and Translational Science Institute (UCLA CTSI) created a Core Voucher program. The underlying premise is that by actively promoting interplay between researchers and core facilities, a dynamic feedback loop could be established that could enhance both groups, the productivity of the former and the relevance of the latter. Our primary goal was to give translational investigators what they need to pursue their immediate projects at hand.

Methods: To implement this system across four noncontiguous campuses, open-source web-accessible software applications were created that were scalable and could efficiently administer investigator submissions and subsequent reviews in a multicampus fashion.

Results: In the past five years, we have processed over 1400 applications submitted by over 750 individual faculty members across both clinical and nonclinical departments. In total, 1926 core requests were made in conjunction with 1467 submitted proposals. The top 10 most popular cores accounted for 50% of all requests, and the top half of the most popular cores accounted for 90% of all requests.

Conclusion: Tracking investigator demand provides a unique window into what are the high- and low-priority core services that best support translational research.
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http://dx.doi.org/10.1017/cts.2019.4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802412PMC
June 2019

Parasite microbiome project: Grand challenges.

PLoS Pathog 2019 10 10;15(10):e1008028. Epub 2019 Oct 10.

Department of Biological Sciences and Northern Gulf Institute, University of Southern Mississippi, Hattiesburg, Mississippi, United States of America.

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http://dx.doi.org/10.1371/journal.ppat.1008028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786532PMC
October 2019

TOX is a critical regulator of tumour-specific T cell differentiation.

Nature 2019 07 17;571(7764):270-274. Epub 2019 Jun 17.

Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Tumour-specific CD8 T cell dysfunction is a differentiation state that is distinct from the functional effector or memory T cell states. Here we identify the nuclear factor TOX as a crucial regulator of the differentiation of tumour-specific T (TST) cells. We show that TOX is highly expressed in dysfunctional TST cells from tumours and in exhausted T cells during chronic viral infection. Expression of TOX is driven by chronic T cell receptor stimulation and NFAT activation. Ectopic expression of TOX in effector T cells in vitro induced a transcriptional program associated with T cell exhaustion. Conversely, deletion of Tox in TST cells in tumours abrogated the exhaustion program: Tox-deleted TST cells did not upregulate genes for inhibitory receptors (such as Pdcd1, Entpd1, Havcr2, Cd244 and Tigit), the chromatin of which remained largely inaccessible, and retained high expression of transcription factors such as TCF-1. Despite their normal, 'non-exhausted' immunophenotype, Tox-deleted TST cells remained dysfunctional, which suggests that the regulation of expression of inhibitory receptors is uncoupled from the loss of effector function. Notably, although Tox-deleted CD8 T cells differentiated normally to effector and memory states in response to acute infection, Tox-deleted TST cells failed to persist in tumours. We hypothesize that the TOX-induced exhaustion program serves to prevent the overstimulation of T cells and activation-induced cell death in settings of chronic antigen stimulation such as cancer.
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http://dx.doi.org/10.1038/s41586-019-1324-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698992PMC
July 2019

TOX transcriptionally and epigenetically programs CD8 T cell exhaustion.

Nature 2019 07 17;571(7764):211-218. Epub 2019 Jun 17.

Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Exhausted CD8 T (T) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (T) or memory (T) CD8 T cells. T cells are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, T cells are a distinct immune subset, with a unique chromatin landscape compared with T and T cells. However, the mechanisms that govern the transcriptional and epigenetic development of T cells remain unknown. Here we identify the HMG-box transcription factor TOX as a central regulator of T cells in mice. TOX is largely dispensable for the formation of T and T cells, but it is critical for exhaustion: in the absence of TOX, T cells do not form. TOX is induced by calcineurin and NFAT2, and operates in a feed-forward loop in which it becomes calcineurin-independent and sustained in T cells. Robust expression of TOX therefore results in commitment to T cells by translating persistent stimulation into a distinct T cell transcriptional and epigenetic developmental program.
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http://dx.doi.org/10.1038/s41586-019-1325-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713202PMC
July 2019

Non-integumentary melanosomes can bias reconstructions of the colours of fossil vertebrates.

Nat Commun 2018 07 23;9(1):2878. Epub 2018 Jul 23.

Department of Chemistry, Fujita Health University School of Health Sciences, Toyoake, Aichi, 470-1192, Japan.

The soft tissues of many fossil vertebrates preserve evidence of melanosomes-micron-scale organelles that inform on integumentary coloration and communication strategies. In extant vertebrates, however, melanosomes also occur in internal tissues. Hence, fossil melanosomes may not derive solely from the integument and its appendages. Here, by analyzing extant and fossil frogs, we show that non-integumentary melanosomes have high fossilization potential, vastly outnumber those from the skin, and potentially dominate the melanosome films preserved in some fossil vertebrates. Our decay experiments show that non-integumentary melanosomes usually remain in situ provided that carcasses are undisturbed. Micron-scale study of fossils, however, demonstrates that non-integumentary melanosomes can redistribute through parts of the body if carcasses are disturbed by currents. Collectively, these data indicate that fossil melanosomes do not always relate to integumentary coloration. Integumentary and non-integumentary melanosomes can be discriminated using melanosome geometry and distribution. This is essential to accurate reconstructions of the integumentary colours of fossil vertebrates.
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http://dx.doi.org/10.1038/s41467-018-05148-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056411PMC
July 2018

Expression of the DNA-Binding Factor TOX Promotes the Encephalitogenic Potential of Microbe-Induced Autoreactive CD8 T Cells.

Immunity 2018 05;48(5):937-950.e8

Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland; Division of Clinical Pathology, Geneva University Hospital, Geneva, Switzerland. Electronic address:

Infections are thought to trigger CD8 cytotoxic T lymphocyte (CTL) responses during autoimmunity. However, the transcriptional programs governing the tissue-destructive potential of CTLs remain poorly defined. In a model of central nervous system (CNS) inflammation, we found that infection with lymphocytic choriomeningitis virus (LCMV), but not Listeria monocytogenes (Lm), drove autoimmunity. The DNA-binding factor TOX was induced in CTLs during LCMV infection and was essential for their encephalitogenic properties, and its expression was inhibited by interleukin-12 during Lm infection. TOX repressed the activity of several transcription factors (including Id2, TCF-1, and Notch) that are known to drive CTL differentiation. TOX also reduced immune checkpoint sensitivity by restraining the expression of the inhibitory checkpoint receptor CD244 on the surface of CTLs, leading to increased CTL-mediated damage in the CNS. Our results identify TOX as a transcriptional regulator of tissue-destructive CTLs in autoimmunity, offering a potential mechanistic link to microbial triggers.
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http://dx.doi.org/10.1016/j.immuni.2018.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040915PMC
May 2018

Alternative activation generates IL-10 producing type 2 innate lymphoid cells.

Nat Commun 2017 12 1;8(1):1900. Epub 2017 Dec 1.

Research Division of Immunology, Departments of Biomedical Sciences and Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA, 90048, USA.

Type 2 innate lymphoid cells (ILC2) share cytokine and transcription factor expression with CD4 T2 cells, but functional diversity of the ILC2 lineage has yet to be fully explored. Here, we show induction of a molecularly distinct subset of activated lung ILC2, termed ILC2. These cells produce IL-10 and downregulate some pro-inflammatory genes. Signals that generate ILC2 are distinct from those that induce IL-13 production, and gene expression data indicate that an alternative activation pathway leads to the generation of ILC2. In vivo, IL-2 enhances ILC2 generation and is associated with decreased eosinophil recruitment to the lung. Unlike most activated ILC2, the ILC2 population contracts after cessation of stimulation in vivo, with maintenance of a subset that can be recalled by restimulation, analogous to T-cell effector cell and memory cell generation. These data demonstrate the generation of a previously unappreciated IL-10 producing ILC2 effector cell population.
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http://dx.doi.org/10.1038/s41467-017-02023-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5711851PMC
December 2017

Development and differentiation of early innate lymphoid progenitors.

J Exp Med 2018 01 28;215(1):249-262. Epub 2017 Nov 28.

Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD

Early innate lymphoid progenitors (EILPs) have recently been identified in mouse adult bone marrow as a multipotential progenitor population specified toward innate lymphoid cell (ILC) lineages, but their relationship with other described ILC progenitors is still unclear. In this study, we examine the progenitor-successor relationships between EILPs, all-lymphoid progenitors (ALPs), and ILC precursors (ILCps). Functional, bioinformatic, phenotypical, and genetic approaches collectively establish EILPs as an intermediate progenitor between ALPs and ILCps. Our work additionally provides new candidate regulators of ILC development and clearly defines the stage of requirement of transcription factors key for early ILC development.
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http://dx.doi.org/10.1084/jem.20170832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748853PMC
January 2018

UniEuk: Time to Speak a Common Language in Protistology!

J Eukaryot Microbiol 2017 05 21;64(3):407-411. Epub 2017 Apr 21.

Sorbonne Universités UPMC Université Paris 06 & CNRS, UMR7144, Station Biologique de Roscoff, Place Georges Teissier, Roscoff, 29680, France.

Universal taxonomic frameworks have been critical tools to structure the fields of botany, zoology, mycology, and bacteriology as well as their large research communities. Animals, plants, and fungi have relatively solid, stable morpho-taxonomies built over the last three centuries, while bacteria have been classified for the last three decades under a coherent molecular taxonomic framework. By contrast, no such common language exists for microbial eukaryotes, even though environmental '-omics' surveys suggest that protists make up most of the organismal and genetic complexity of our planet's ecosystems! With the current deluge of eukaryotic meta-omics data, we urgently need to build up a universal eukaryotic taxonomy bridging the protist -omics age to the fragile, centuries-old body of classical knowledge that has effectively linked protist taxa to morphological, physiological, and ecological information. UniEuk is an open, inclusive, community-based and expert-driven international initiative to build a flexible, adaptive universal taxonomic framework for eukaryotes. It unites three complementary modules, EukRef, EukBank, and EukMap, which use phylogenetic markers, environmental metabarcoding surveys, and expert knowledge to inform the taxonomic framework. The UniEuk taxonomy is directly implemented in the European Nucleotide Archive at EMBL-EBI, ensuring its broad use and long-term preservation as a reference taxonomy for eukaryotes.
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http://dx.doi.org/10.1111/jeu.12414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435949PMC
May 2017

Probing the evolution, ecology and physiology of marine protists using transcriptomics.

Nat Rev Microbiol 2017 01 21;15(1):6-20. Epub 2016 Nov 21.

Canadian Institute for Advanced Research, 180 Dundas Street W, Toronto, Ontario M5G 1Z8, Canada.

Protists, which are single-celled eukaryotes, critically influence the ecology and chemistry of marine ecosystems, but genome-based studies of these organisms have lagged behind those of other microorganisms. However, recent transcriptomic studies of cultured species, complemented by meta-omics analyses of natural communities, have increased the amount of genetic information available for poorly represented branches on the tree of eukaryotic life. This information is providing insights into the adaptations and interactions between protists and other microorganisms and macroorganisms, but many of the genes sequenced show no similarity to sequences currently available in public databases. A better understanding of these newly discovered genes will lead to a deeper appreciation of the functional diversity and metabolic processes in the ocean. In this Review, we summarize recent developments in our understanding of the ecology, physiology and evolution of protists, derived from transcriptomic studies of cultured strains and natural communities, and discuss how these novel large-scale genetic datasets will be used in the future.
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http://dx.doi.org/10.1038/nrmicro.2016.160DOI Listing
January 2017

Differentiation of Murine Innate Lymphoid Cells from Common Lymphoid Progenitor Cells.

Bio Protoc 2016 Mar;6(6)

Research Division of Immunology, Departments of Biomedical Sciences and Medicine, Cedars Sinai Medical Center, Los Angeles, USA.

Subtypes of innate lymphoid cells (ILC), defined based on their cytokine secretion profiles and transcription factor expression, are important for host protection from pathogens and maintaining tissue homeostasis. ILCs develop from common lymphoid progenitors (CLP) in the bone marrow. Using the methods described here, we have previously shown that loss of the transcriptional regulator TOX (Thymocyte-selection associated HMG-box protein) leads to specific changes in ILC development and differentiation. Here, we describe how to obtain ILCs from isolated CLP grown .
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880359PMC
http://dx.doi.org/10.21769/bioprotoc.1770DOI Listing
March 2016

The Role of TOX in the Development of Innate Lymphoid Cells.

Mediators Inflamm 2015 18;2015:243868. Epub 2015 Oct 18.

Research Division of Immunology, Departments of Biomedical Sciences and Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA ; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.

TOX, an evolutionarily conserved member of the HMG-box family of proteins, is essential for the development of various cells of both the innate and adaptive immune system. TOX is required for the development of CD4(+) T lineage cells in the thymus, including natural killer T and T regulatory cells, as well as development of natural killer cells and fetal lymphoid tissue inducer cells, the latter required for lymph node organogenesis. Recently, we have identified a broader role for TOX in the innate immune system, demonstrating that this nuclear protein is required for generation of bone marrow progenitors that have potential to give rise to all innate lymphoid cells. Innate lymphoid cells, classified according to transcription factor expression and cytokine secretion profiles, derive from common lymphoid progenitors in the bone marrow and require Notch signals for their development. We discuss here the role of TOX in specifying CLP toward an innate lymphoid cell fate and hypothesize a possible role for TOX in regulating Notch gene targets during innate lymphoid cell development.
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http://dx.doi.org/10.1155/2015/243868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4628649PMC
September 2016

ILC development: TCF-1 reporting in.

Authors:
Jonathan Kaye

Nat Immunol 2015 Oct;16(10):1011-2

Research Division of Immunology, Departments of Biomedical Sciences and Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA, and the Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA.

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http://dx.doi.org/10.1038/ni.3276DOI Listing
October 2015

The development of innate lymphoid cells requires TOX-dependent generation of a common innate lymphoid cell progenitor.

Nat Immunol 2015 Jun 27;16(6):599-608. Epub 2015 Apr 27.

1] Research Division of Immunology, Departments of Biomedical Sciences and Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. [2] Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA.

Diverse innate lymphoid cell (ILC) subtypes have been defined on the basis of effector function and transcription factor expression. ILCs derive from common lymphoid progenitors, although the transcriptional pathways that lead to ILC-lineage specification remain poorly characterized. Here we found that the transcriptional regulator TOX was required for the in vivo differentiation of common lymphoid progenitors into ILC lineage-restricted cells. In vitro modeling demonstrated that TOX deficiency resulted in early defects in the survival or proliferation of progenitor cells, as well as ILC differentiation at a later stage. In addition, comparative transcriptome analysis of bone marrow progenitors revealed that TOX-deficient cells failed to upregulate many genes of the ILC program, including genes that are targets of Notch, which indicated that TOX is a key determinant of early specification to the ILC lineage.
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http://dx.doi.org/10.1038/ni.3168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4439271PMC
June 2015

TOX3 is expressed in mammary ER(+) epithelial cells and regulates ER target genes in luminal breast cancer.

BMC Cancer 2015 Jan 30;15:22. Epub 2015 Jan 30.

Research Division of Immunology, Departments of Biomedical Sciences and Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Davis 5089, Los Angeles, 90048, CA, USA.

Background: A breast cancer susceptibility locus has been mapped to the gene encoding TOX3. Little is known regarding the expression pattern or biological role of TOX3 in breast cancer or in the mammary gland. Here we analyzed TOX3 expression in murine and human mammary glands and in molecular subtypes of breast cancer, and assessed its ability to alter the biology of breast cancer cells.

Methods: We used a cell sorting strategy, followed by quantitative real-time PCR, to study TOX3 gene expression in the mouse mammary gland. To study the expression of this nuclear protein in human mammary glands and breast tumors, we generated a rabbit monoclonal antibody specific for human TOX3. In vitro studies were performed on MCF7, BT474 and MDA-MB-231 cell lines to study the effects of TOX3 modulation on gene expression in the context of breast cancer cells.

Results: We found TOX3 expression in estrogen receptor-positive mammary epithelial cells, including progenitor cells. A subset of breast tumors also highly expresses TOX3, with poor outcome associated with high expression of TOX3 in luminal B breast cancers. We also demonstrate the ability of TOX3 to alter gene expression in MCF7 luminal breast cancer cells, including cancer relevant genes TFF1 and CXCR4. Knockdown of TOX3 in a luminal B breast cancer cell line that highly expresses TOX3 is associated with slower growth. Surprisingly, TOX3 is also shown to regulate TFF1 in an estrogen-independent and tamoxifen-insensitive manner.

Conclusions: These results demonstrate that high expression of this protein likely plays a crucial role in breast cancer progression. This is in sharp contrast to previous studies that indicated breast cancer susceptibility is associated with lower expression of TOX3. Together, these results suggest two different roles for TOX3, one in the initiation of breast cancer, potentially related to expression of TOX3 in mammary epithelial cell progenitors, and another role for this nuclear protein in the progression of cancer. In addition, these results can begin to shed light on the reported association of TOX3 expression and breast cancer metastasis to the bone, and point to TOX3 as a novel regulator of estrogen receptor-mediated gene expression.
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http://dx.doi.org/10.1186/s12885-015-1018-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4324787PMC
January 2015

The many roles of TOX in the immune system.

Curr Opin Immunol 2012 Apr 30;24(2):173-7. Epub 2011 Dec 30.

Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

TOX is a member of an evolutionarily conserved DNA-binding protein family and is expressed in several immune-relevant cell subsets. Here, we review the key role of TOX in regulating development of CD4 T cells, natural killer cells and lymphoid tissue inducer cells, the latter responsible for the generation of lymph nodes. Although the exact molecular mechanism of action of TOX remains to be elucidated, the role of TOX in establishment of gene programs in the thymus and the potential of TOX as a regulator of E protein activity are discussed.
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http://dx.doi.org/10.1016/j.coi.2011.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319641PMC
April 2012

Selective endoscopic treatment of the non-refluxing contralateral ureter prevents new contralateral vesicoureteral reflux.

J Pediatr Urol 2013 Feb 15;9(1):51-5. Epub 2011 Dec 15.

Pediatric Urology at Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30342, USA.

Objective: The objective of this study was to evaluate risk factors for new contralateral vesicoureteral reflux (NCVUR) and to investigate whether assessment of the non-refluxing contralateral ureter (NRCU) by hydrodistention and selective treatment can reduce the incidence of NCVUR.

Materials And Methods: From 2001 to 2007, 339 of 841 patients (40%) were treated for unilateral VUR by endoscopic injection. While in the first 267 patients the NRCU was only assessed by hydrodistention but not injected (observation group), NRCUs of the subsequent 72 patients were prophylactically treated if deemed at high risk for NCVUR (H2 or H3) (prophylaxis group).

Results: NCVUR occurred in 30 of 267 patients (11.2%) whose NRCUs were observed. No statistically significant risk factors for NCVUR were found in this group. In the subsequent 72 patients, whose H2 and H3 ureters were selectively injected (N = 56), no cases of NCVUR were seen.

Conclusions: Prophylactic endoscopic treatment of NRCU H2 and H3 ureters successfully prevented the occurrence of NCVUR.
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http://dx.doi.org/10.1016/j.jpurol.2011.11.013DOI Listing
February 2013

Pediatric chronic orchalgia.

J Pediatr Urol 2012 Aug 4;8(4):421-5. Epub 2011 Nov 4.

Emory University School of Medicine, Atlanta, 5445 Meridian Mark Road, Suite 420, Atlanta, GA 30342, USA.

Introduction: Chronic orchalgia, defined as testicular pain lasting > 3 months and interfering with normal activities, is neglected in the pediatric literature. We describe our experience with the evaluation and treatment of pediatric chronic orchalgia patients.

Materials And Methods: Charts were screened to identify patients meeting the criteria for chronic orchalgia. Charts were further reviewed to record the history and physical exam, diagnostic tests, treatment and outcomes.

Results: 65/982 patients met the criteria for chronic orchalgia. Mean age was 13 and mean duration of pain was 8.6 months. Physical exam findings were normal in 46 patients (70%). 59 patients were managed conservatively with resolution (10/59, 17%) or a single visit (36/59, 61%) in 78%. 13/59 (22%) patients showed either minor improvement or no change in symptoms. 5 non-responding patients were managed by the anesthesia pain service; 4 received epidurals with or without additional oral pain medications with 3 experiencing significant pain improvement.

Conclusion: Conservative management of chronic orchalgia allowed symptoms to subside in the majority of cases. We recommend patients be treated with conservative measures for 1-2 months. If this fails, early involvement of the anesthesia pain service can offer treatment modalities such as epidural analgesia. Surgical management in the face of a normal physical exam does not seem to have a role.
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http://dx.doi.org/10.1016/j.jpurol.2011.09.002DOI Listing
August 2012

TOX is required for development of the CD4 T cell lineage gene program.

J Immunol 2011 Dec 21;187(11):5931-40. Epub 2011 Oct 21.

Research Division of Immunology, Department of Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

The factors that regulate thymic development of the CD4(+) T cell gene program remain poorly defined. The transcriptional regulator ThPOK is a dominant factor in CD4(+) T cell development, which functions primarily to repress the CD8 lineage fate. Previously, we showed that nuclear protein TOX is also required for murine CD4(+) T cell development. In this study, we sought to investigate whether the requirement for TOX was solely due to a role in ThPOK induction. In apparent support of this proposition, ThPOK upregulation and CD8 lineage repression were compromised in the absence of TOX, and enforced ThPOK expression could restore some CD4 development. However, these "rescued" CD4 cells were defective in many aspects of the CD4(+) T cell gene program, including expression of Id2, Foxo1, and endogenous Thpok, among others. Thus, TOX is necessary to establish the CD4(+) T cell lineage gene program, independent of its influence on ThPOK expression.
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http://dx.doi.org/10.4049/jimmunol.1101474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3221881PMC
December 2011

Intermediate to long-term follow-up indicates low risk of recurrence after Double HIT endoscopic treatment for primary vesico-ureteral reflux.

J Pediatr Urol 2012 Aug 4;8(4):359-65. Epub 2011 Aug 4.

Children's Healthcare of Atlanta and Emory University School of Medicine, 5445 Meridian Mark Rd, Atlanta, GA 30342, USA.

Purpose: Follow-up of patients undergoing dextranomer/hyaluronic acid injection for vesico-ureteral reflux (VUR) is controversial. The purpose of our study was to test the hypothesis that patients undergoing the double hydrodistention-implantation technique (Double HIT) have a higher clinical and radiographic success rate.

Materials And Methods: Patients undergoing Double HIT endoscopic injection for VUR were prospectively identified. Patients underwent an ultrasound at 6 weeks to assess the implants, and, if visible, prophylactic antibiotics were discontinued and patients were scheduled for a 1-year voiding cystourethrogram (VCUG). Radiographic success was defined as a negative VCUG and clinical success as no febrile urinary tract infections at 1 year.

Results: A total of 54 patients underwent endoscopic injection for VUR. Twenty-five (51%) were compliant with the 1 year follow-up; 18 non-compliant patients were contacted and their clinical status assessed. Thirty patients eventually completed the 1-year VCUG at a mean of 12.2 months (range 10-20). Among the 60% of patients with 1-year radiographic follow-up, 2 had persistent VUR for a radiologic success rate of 93%. All radiographic failures were infection-free. Of the 80% (43/54) of patients with available clinical data, 3 (7%) had afebrile UTI for a clinical success rate of 93%.

Conclusions: The Double HIT leads to a 93% clinical and 93% radiographic intermediate/long-term success rate. With this technique, better outcomes were achieved with fewer recurrences than previously reported. These favorable results challenge the need for postoperative VCUG in asymptomatic patients after the Double HIT.
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http://dx.doi.org/10.1016/j.jpurol.2011.07.006DOI Listing
August 2012

Pediatric adrenal trauma in the 21st century: Children's Hospital of Atlanta experience.

J Urol 2011 Jul 14;186(1):248-51. Epub 2011 May 14.

Department of Urology, Emory University School of Medicine, Children's Hospitals of Atlanta, Atlanta, Georgia, USA.

Purpose: Adrenal trauma in children is rare and poorly characterized. To characterize these injuries better, we reviewed the contemporary experience at a large pediatric trauma center.

Materials And Methods: We queried the trauma registry of Children's Hospitals of Atlanta for all patients treated for adrenal trauma (ICD-9 codes 868.01 and 868.11) between January 1, 2000 and December 31, 2009. We performed a detailed chart review.

Results: Of 12,045 patients who were treated for trauma during the study period 42 children (0.35%) with adrenal injuries were identified. All injuries resulted from blunt trauma. Motor vehicle crash was the most common mechanism, responsible for 41% of injuries. A total of 41 cases (98%) were diagnosed by computerized tomography and 1 during exploratory laparotomy for associated vascular injury. Injuries were to the right adrenal gland in 36 cases (86%), left in 5 (12%) and bilateral in 1 (2%). The most common associated regions were the liver (55%), head or brain (33%) and skeleton (31%). Five patients (12%) experienced isolated adrenal injuries. One patient required treatment for adrenal insufficiency and none required adrenalectomy, adrenalorrhaphy or adrenal embolization. Of patients with isolated adrenal injuries 2 were hospitalized and 3 were treated as outpatients. All had an unremarkable course.

Conclusions: Adrenal trauma in children is rare. Although typically associated with high morbidity, this outcome is likely from related injuries as an isolated adrenal injury generally portends a benign course.
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http://dx.doi.org/10.1016/j.juro.2011.03.047DOI Listing
July 2011

Clinical and radiographic results of endoscopic injection for vesicoureteral reflux: defining measures of success.

J Pediatr Urol 2012 Jun 4;8(3):297-303. Epub 2011 May 4.

Department of Pediatric Urology, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30342, USA.

Objective: Criteria for success following endoscopic vesicoureteral reflux (VUR) surgery vary greatly. We sought to define outcomes based on radiographic and long-term clinical follow up.

Methods: We reviewed the charts and interviewed parents of children who underwent endoscopic treatment for primary VUR (grades I-IV). All patients had a postoperative voiding cystourethrogram (VCUG) at mean of 3 months (1-21 months) and all cases of postoperative febrile urinary tract infection (FUTI) prompted repeat VCUG. Radiographic success was defined as no VUR on postoperative VCUG and clinical success as no FUTIs during follow up of 12-36 months. To demonstrate how criteria for success can affect outcomes, we calculated the success rates using different definitions.

Results: In 2004-2008, 336 patients (296 female and 40 male, mean age 4 years) were treated with dextranomer/hyaluronic acid via the Double-HIT method. Initial radiographic success was 90% (302/336). Of these, 19 (6%) developed FUTIs, 12 (4%) of whom had recurrent VUR, and 5 (2%) went on to open surgery. Of the radiographic failures, 18% were observed with no further treatment. Success defined clinically was 94% (281/300), and as 'radiographic cure and no clinical evidence of FUTIs' it was 82% (275/336).

Conclusions: It is important to agree on a universal definition of success for VUR interventions to compare across studies and across therapies. Clinical success is more meaningful to the patient, and initial radiographic success could be followed by UTI necessitating further intervention. We question the need for routine postoperative VCUG.
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http://dx.doi.org/10.1016/j.jpurol.2011.02.006DOI Listing
June 2012

Does compliance status predict clinical status in patients undergoing endoscopic management of vesico-ureteral reflux?

J Pediatr Urol 2011 Dec 29;7(6):644-9. Epub 2011 Apr 29.

Children's Healthcare of Atlanta, Emory University School of Medicine, Pediatric Urology, Atlanta, GA 30342, USA.

Objective: Previous studies of endoscopic management of vesico-ureteral reflux (VUR) have had non-compliance rates around 50%. We examined success rates of patients non-compliant with a delayed follow up protocol after endoscopic injection for VUR.

Materials And Methods: Patients undergoing Double HIT, dextranomer/hyaluronic acid copolymer endoscopic injection for VUR were enrolled in a 1-year, delayed voiding cysto-urethrogram (VCUG) study. All patients non-compliant with the VCUG were contacted and information on their clinical status was collected. Non-compliant patients were re-scheduled for a VCUG.

Results: 49/54 (91%) patients underwent endoscopic injection for VUR and completed the 6-week ultrasound. At 1-year 49% (24/49) were non-compliant with a VCUG; 75% (18/24) were contacted and provided clinical information. All but one patient agreed to the VCUG. Patients compliant with the 1-year VCUG showed 96% (24/25) clinical and 92% (23/25) radiologic success rates. Non-compliant patients had an 89% (16/18) clinical success rate; 5 (21%) non-compliant patients underwent VCUGs with a 100% success rate.

Conclusions: Long-term compliance remains an issue for patients treated endoscopically for VUR, but compliance does not predict clinical status as both groups have favorable clinical outcomes. The repeat VCUG is a barrier to long-term follow up as only 21% of patients underwent the study.
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http://dx.doi.org/10.1016/j.jpurol.2011.03.012DOI Listing
December 2011

Rotation of the amputated fistula tract for the management of congenital urethral-enteric fistula with severe urethral stenosis: a novel technique with long-term outcomes.

J Pediatr Urol 2012 Apr 20;8(2):166-73. Epub 2011 Apr 20.

Department of Pediatric Urology, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA.

Objective: Urethral-enteric fistulae with hypoplastic/atretic distal urethra in boys with anorectal malformations are amenable to management via sequential dilation of the distal urethra (P.A.D.U.A.) and subsequent repair of the fistula, but failure of this technique occasionally requires complex reconstruction. We present a novel surgical approach, along with long-term results, that incorporates rotation of the amputated fistula tract (RAFT) in boys with H-type urethral-enteric fistulae.

Methods: The charts of four patients undergoing the RAFT procedure were reviewed. All had previously failed P.A.D.U.A. Surgical principles were similar in all cases: the fistula tract was amputated as close to the bowel as possible. A tubularized or on-layed urethra was then fashioned from preputial skin and anastomosed to the distal end of the urethral fistula. The distal end of the neourethra was then brought to the tip of the penis, or anastomosed to the proximal end of the patent distal urethra.

Results: Mean age was 12.3 months, and there was a mean follow up of 10.2 years. All four patients had a rectourethral fistula as a component of VACTERL, with a urethral deficit of 7-11 cm. All had a functionally intact urethra on reconstruction, with normal continence and bladder neck closure. Two patients needed further bladder augmentation with a Mitrofanoff channel for poor bladder compliance. Both boys who were post-pubertal in this series report normal sexual function with antegrade ejaculation.

Conclusions: The RAFT technique represents a viable reconstructive option for congenital H-fistulae with distal urethral stenosis, with excellent long-term results. It provides boys with normal urethral function, along with intact urinary continence and antegrade ejaculation. This technique may be of particular utility in patients after failed P.A.D.U.A., or in whom a staged buccal onlay graft is not feasible.
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http://dx.doi.org/10.1016/j.jpurol.2011.02.033DOI Listing
April 2012