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      PAX1 is essential for development and function of the human thymus

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          Abstract

          We investigated the molecular and cellular basis of severe combined immunodeficiency (SCID) in six patients with otofaciocervical syndrome type 2 who failed to attain T cell reconstitution after allogeneic hematopoietic stem cell transplantation, despite successful engraftment in three of them. We identified rare bi-allelic PAX1 rare variants in all patients. We demonstrated that these mutant PAX1 proteins have an altered conformation and flexibility of the paired box domain and reduced transcriptional activity. We generated patient-derived induced pluripotent stem cells and differentiated them into thymic epithelial progenitor cells, and found that they have an altered transcriptional profile, including for genes involved in the development of the thymus and other tissues derived from pharyngeal pouches. These results identify bi-allelic, loss-of-function PAX1 mutations as the cause of a syndromic form of SCID due to altered thymus development.

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          PAX1 deficiency causes a syndromic form of SCID by altering differentiation of thymic epithelial cells and other pharyngeal pouch tissues.

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          p63 Is essential for the proliferative potential of stem cells in stratified epithelia.

          Makoto Senoo, Filipa C.S.C. Pinto, Christopher Crum … (2007)
          The distinguishing feature of adult stem cells is their extraordinary capacity to divide prior to the onset of senescence. While stratified epithelia such as skin, prostate, and breast are highly regenerative and account disproportionately for human cancers, genes essential for the proliferative capacity of their stem cells remain unknown. Here we analyze p63, a gene whose deletion in mice results in the catastrophic loss of all stratified epithelia. We demonstrate that p63 is strongly expressed in epithelial cells with high clonogenic and proliferative capacity and that stem cells lacking p63 undergo a premature proliferative rundown. Additionally, we show that p63 is dispensable for both the commitment and differentiation of these stem cells during tissue morphogenesis. Together, these data identify p63 as a key, lineage-specific determinant of the proliferative capacity in stem cells of stratified epithelia.
          Article 0 comments Cited 268 times – based on 0 reviews     Review now
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            Infectious disease. Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency.

            Michael J Ciancanelli, Sarah X L Huang, Priya Luthra … (2015)
            Severe influenza disease strikes otherwise healthy children and remains unexplained. We report compound heterozygous null mutations in IRF7, which encodes the transcription factor interferon regulatory factor 7, in an otherwise healthy child who suffered life-threatening influenza during primary infection. In response to influenza virus, the patient's leukocytes and plasmacytoid dendritic cells produced very little type I and III interferons (IFNs). Moreover, the patient's dermal fibroblasts and induced pluripotent stem cell (iPSC)-derived pulmonary epithelial cells produced reduced amounts of type I IFN and displayed increased influenza virus replication. These findings suggest that IRF7-dependent amplification of type I and III IFNs is required for protection against primary infection by influenza virus in humans. They also show that severe influenza may result from single-gene inborn errors of immunity. Copyright © 2015, American Association for the Advancement of Science.
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              Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment

              Ute Koch, Emma Fiorini, Rui Benedito … (2008)
              Thymic T cell lineage commitment is dependent on Notch1 (N1) receptor–mediated signaling. Although the physiological ligands that interact with N1 expressed on thymic precursors are currently unknown, in vitro culture systems point to Delta-like 1 (DL1) and DL4 as prime candidates. Using DL1- and DL4-lacZ reporter knock-in mice and novel monoclonal antibodies to DL1 and DL4, we show that DL4 is expressed on thymic epithelial cells (TECs), whereas DL1 is not detected. The function of DL4 was further explored in vivo by generating mice in which DL4 could be specifically inactivated in TECs or in hematopoietic progenitors. Although loss of DL4 in hematopoietic progenitors did not perturb thymus development, inactivation of DL4 in TECs led to a complete block in T cell development coupled with the ectopic appearance of immature B cells in the thymus. These immature B cells were phenotypically indistinguishable from those developing in the thymus of conditional N1 mutant mice. Collectively, our results demonstrate that DL4 is the essential and nonredundant N1 ligand responsible for T cell lineage commitment. Moreover, they strongly suggest that N1-expressing thymic progenitors interact with DL4-expressing TECs to suppress B lineage potential and to induce the first steps of intrathymic T cell development.
              Article 0 comments Cited 150 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 101688624
                Journal ID (pubmed-jr-id): 45516
                Journal ID (nlm-ta): Sci Immunol
                Journal ID (iso-abbrev): Sci Immunol
                Title: Science immunology
                ISSN (Electronic): 2470-9468
                Publication date Nihms-submitted: 13 April 2020
                Publication date (Print): 28 February 2020
                Publication date PMC-release: 28 August 2020
                Volume: 5
                Issue: 44
                Electronic Location Identifier: eaax1036
                Affiliations
                [1 ]Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD 20892, USA
                [2 ]Human and Molecular Genetics Center, Medical College Wisconsin, Milwaukee, MI, USA
                [3 ]Systemic Autoimmunity Branch, NIAMS, NIH, Bethesda, MD 20892, USA
                [4 ]Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
                [5 ]Cytogenetic and Medical Genetics Unit, “A. Nocivelli” Institute for Molecular Medicine, Spedali Civili Hospital, Brescia, Italy
                [6 ]Coyote Bioscience USA Inc., San Jose, CA 95138, USA
                [7 ]Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, College of Medicine, Cincinnati, OH 45229, USA
                [8 ]Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
                [9 ]Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
                [10 ]Division of Pediatric Allergy and Immunology, Mayo Clinic Children’s Center, Rochester, MN, USA
                [11 ]Genomic Technologies Section, NIAID, NIH, Bethesda, MD 20892, USA
                [12 ]Research Technologies Branch, DIR, NIAID, NIH, Bethesda, MD 20892, USA
                [13 ]Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
                [14 ]Department of Radiology, Mayo Clinic, Rochester, MN, USA
                [15 ]Alfaisal University, Riyadh, Saudi Arabia
                [16 ]GeneDx Inc., Gaithersburg, MD 20877, USA
                [17 ]PerkinElmer Genomics, Pittsburgh, PA 15275, USA
                [18 ]Cancer and Blood Institute, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, College of Medicine, Cincinnati, OH 45229, USA
                [19 ]St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA
                [20 ]Laboratory of Human Genetics of Infectious Diseases, Necker Branch INSERM, Necker Hospital for Sick Children, Paris, France
                [21 ]Paris Descartes University, Imagine Institute, Paris, France
                [22 ]Pediatric Immunology, Department of Health Sciences, University of Florence, Florence, Italy
                [23 ]Meyer Children’s Hospital, Florence, Italy
                [24 ]Department of Pediatrics, Allergy and Immunology Section, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
                [25 ]Pediatrics Hematology-Immunology Unit, Necker Hospital for Sick Children, Paris, France
                [26 ]Howard Hughes Medical Institute, New York, NY 10065, USA
                [27 ]Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
                [28 ]Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, OH 43205, USA
                [29 ]Department of Geriatrics, West China Hospital, Sichuan University, Chengdu, China
                [30 ]Aperiomics, Inc., Sterling, VA 20166, USA
                Author notes

                Author contributions: YY performed experiments and wrote the manuscript; RU performed structural modeling and molecular dynamics simulation studies; LF supervised analysis of RNAseq and GSEA data; FO-C and TM assisted with RNAseq studies; SG and SM performed Sanger sequencing and Western blot analysis, and analyzed WES data; KZ, AMA, HA, FZ, CAV and BB performed and analyzed WES; AKD generated iPSCs; AJ, RWM, AHF, CA, BKA-S, and H-AM provided clinical care and description of the patients; FF performed lymph node pathology; MPB, MLH and CM performed and interpreted imaging studies; JLC and RSA contributed to supervision of the project and to writing of the manuscript; LDN was responsible for the entire research project and wrote the manuscript.

                [* ]Corresponding author. luigi.notarangelo2@ 123456nih.gov
                Article
                Accession ID: PMC7189207 Pmcid ID: PMC7189207 Pmc-uid ID: 7189207 Manuscript ID: nihpa1582685
                DOI: 10.1126/sciimmunol.aax1036
                PMC ID: 7189207
                PubMed ID: 32111619
                SO-VID: b372b1e6-e9c9-44d8-8a04-ad8eac03d403
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