Inborn errors of thymic stromal cell development and function
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REVIEW
Inborn errors of thymic stromal cell development and function Alexandra Y. Kreins 1,2
&
Stefano Maio 3
&
Fatima Dhalla 3,4
Received: 30 July 2020 / Accepted: 9 November 2020 # The Author(s) 2020
Abstract As the primary site for T cell development, the thymus is responsible for the production and selection of a functional, yet selftolerant T cell repertoire. This critically depends on thymic stromal cells, derived from the pharyngeal apparatus during embryogenesis. Thymic epithelial cells, mesenchymal and vascular elements together form the unique and highly specialised microenvironment required to support all aspects of thymopoiesis and T cell central tolerance induction. Although rare, inborn errors of thymic stromal cells constitute a clinically important group of conditions because their immunological consequences, which include autoimmune disease and T cell immunodeficiency, can be life-threatening if unrecognised and untreated. In this review, we describe the molecular and environmental aetiologies of the thymic stromal cell defects known to cause disease in humans, placing particular emphasis on those with a propensity to cause thymic hypoplasia or aplasia and consequently severe congenital immunodeficiency. We discuss the principles underpinning their diagnosis and management, including the use of novel tools to aid in their identification and strategies for curative treatment, principally transplantation of allogeneic thymus tissue. Keywords Thymus . Thymic stromal cells . Immunodeficiency . DiGeorge syndrome . FOXN1 . Thymus transplantation
Introduction The thymus is the primary lymphoid organ responsible for the generation and selection of a T cell repertoire able to respond to foreign antigens whilst remaining tolerant to self [1]. In terms of cellular composition, the thymus is mainly comprised of developing thymocytes [2, 3]. It is, however, structurally and functionally dependent on rare stromal cell populations, the main constituent of which are endodermally derived thymic epithelial cells (TEC) [2, 4]. TEC form a specialised three-dimensional scaffold and can be categorised into two main lineages,
This article is a contribution to the special issue on: The thymus and autoimmunity - Guest Editor: Georg Holländer * Fatima Dhalla [email protected] 1
UCL Great Ormond Street Institute of Child Health, London, UK
2
Department of Immunology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
3
Developmental Immunology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
4
Department of Clinical Immunology, Oxford University Hospitals, Oxford, UK
cortical (c-) and medullary (m-) TEC, based on anatomical, molecular and functional characteristics [5–7]. Aside from TEC, the thymic stroma includes mesenchymal and vascular elements. As a composite, these stromal cells form a unique microenvironment enabling homing of lymphoid progenitors to the thymus, where TEC support their commitment to a T cell fate, their differentiati
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