Thymic Epithelial Cell Alterations and Defective Thymopoiesis Lead to Central and Peripheral Tolerance Perturbation in MHCII Deficiency

Frontiers in Immunology

卷:12

Pietro Luigi Poliani¹  Sara Signa²  Blachy J. Dávila Saldaña⁴  Capucine Picard⁵  Tom Taghon⁶  Ottavia M. Delmonte⁷  Luigi D. Notarangelo⁷  Victoria Bordon⁸  Chaim M. Roifman⁹  Paolo Uva¹⁰  Ansgar S. Schulz¹¹  Pier Luigi Mauri¹²  Catharina Schuetz¹³  Silvia Giliani¹⁴  Annarosa Soresina¹⁵  Andrew R. Gennery¹⁷  Francesca Brambilla¹⁸  Dario Di Silvestre¹⁸  Gloria Delfanti²⁰  Despina Moshous²²  Rosita Rigoni²³  Elena Fontana²³  Maria Carmina Castiello²³  Genni Enza Marcovecchio²⁵  Elena Draghici²⁵  Ileana Bortolomai²⁵  Marita Bosticardo²⁵  Anna Villa²⁵  Francesca Ferrua²⁶ 

[1] Allergy, Department of Pediatrics, The Hospital for Sick Children, the Canadian Centre for Primary Immunodeficiency and the University of Toronto, Toronto, ON, Canada;

[2] 0Autoinflammatory Diseases and Immunodeficiencies Center, IRCCS Istituto G. Gaslini, and Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Children's Sciences, University of Genoa, Genoa, Italy;

[3] 0Centre d’Etude des Déficits Immunitaires, Necker-Enfants Malades Hospital, AP-HP, Paris, France;

[4] 1Division of Blood and Marrow Transplantation, Children's National Hospital, Washington, DC, United States;

[5] 1Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Inserm UMR 1163, University Paris Descartes Sorbonne Paris Cité, Imagine Institute, Paris, France;

[6] 2Department of Diagnostic Sciences, Ghent University Hospital, Ghent University, Ghent, Belgium;

[7] 2Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, United States;

[8] 3Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium;

[9] 3Division of Immunology &

[10] 4Department of Molecular and Translational Medicine, Pathology Unit, University of Brescia, Brescia, Italy;

[11] 4Department of Pediatrics, University Medical Center Ulm, Ulm, Germany;

[12] 5CRS4, Science and Technology Park Polaris, Pula, Cagliari, Italy;

[13] 5Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany;

[14] 6Cytogenetics and Medical Genetics Unit and “A. Nocivelli” Institute for Molecular Medicine, Spedali Civili Hospital, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy;

[15] 7Unit of Pediatric Immunology, Pediatrics Clinic, University of Brescia, ASST-Spedali Civili Brescia, Brescia, Italy;

[16] 8Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom;

[17] 9Department of Pediatric Immunology and HSCT, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom;

[18] Department of Biomedical Sciences, Institute for Biomedical Technologies-National Research Council (CNR), Milan, Italy;

[19] Department of Pediatric Immunology, Hematology and Rheumatology, Necker Children’s Hospital, AP-HP, Paris, France;

[20] Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy;

[21] Human Genome Department, Humanitas Clinical and Research Center, Rozzano, Milan, Italy;

[22] Laboratory “Genome Dynamics in the Immune System”, INSERM UMR1163, Université de Paris, Institut Imagine, Paris, France;

[23] Milan Unit, Institute of Genetic and Biomedical Research, National Research Council (CNR), Milan, Italy;

[24] Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy;

[25] San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy;

[26] Vita-Salute San Raffaele University, Milan, Italy;

关键词: thymus;    thymic epithelial cells;    primary immunodeficiency;    MHCII;    central tolerance;   

DOI  :  10.3389/fimmu.2021.669943

来源: DOAJ

【 摘 要 】

Major Histocompatibility Complex (MHC) class II (MHCII) deficiency (MHCII-D), also known as Bare Lymphocyte Syndrome (BLS), is a rare combined immunodeficiency due to mutations in genes regulating expression of MHCII molecules. MHCII deficiency results in impaired cellular and humoral immune responses, leading to severe infections and autoimmunity. Abnormal cross-talk with developing T cells due to the absence of MHCII expression likely leads to defects in thymic epithelial cells (TEC). However, the contribution of TEC alterations to the pathogenesis of this primary immunodeficiency has not been well characterized to date, in particular in regard to immune dysregulation. To this aim, we have performed an in-depth cellular and molecular characterization of TEC in this disease. We observed an overall perturbation of thymic structure and function in both MHCII−/− mice and patients. Transcriptomic and proteomic profiling of murine TEC revealed several alterations. In particular, we demonstrated that impairment of lymphostromal cross-talk in the thymus of MHCII−/− mice affects mTEC maturation and promiscuous gene expression and causes defects of central tolerance. Furthermore, we observed peripheral tolerance impairment, likely due to defective Treg cell generation and/or function and B cell tolerance breakdown. Overall, our findings reveal disease-specific TEC defects resulting in perturbation of central tolerance and limiting the potential benefits of hematopoietic stem cell transplantation in MHCII deficiency.

【 授权许可】

Unknown