Thymic origins of autoimmunity—lessons from inborn errors of immunity
Open Access
- 2 February 2021
- journal article
- review article
- Published by Springer Science and Business Media LLC in Seminars in Immunopathology
- Vol. 43 (1), 65-83
- https://doi.org/10.1007/s00281-020-00835-8
Abstract
During their intrathymic development, nascent T cells are empowered to protect against pathogens and to be operative for a life-long acceptance of self. While autoreactive effector T (Teff) cell progenitors are eliminated by clonal deletion, the intrathymic mechanisms by which thymic regulatory T cell (tTreg) progenitors maintain specificity for self-antigens but escape deletion to exert their regulatory functions are less well understood. Both tTreg and Teff development and selection result from finely coordinated interactions between their clonotypic T cell receptors (TCR) and peptide/MHC complexes expressed by antigen-presenting cells, such as thymic epithelial cells and thymic dendritic cells. tTreg function is dependent on expression of the FOXP3 transcription factor, and induction of FOXP3 gene expression by tTreg occurs during their thymic development, particularly within the thymic medulla. While initial expression of FOXP3 is downstream of TCR activation, constitutive expression is fixed by interactions with various transcription factors that are regulated by other extracellular signals like TCR and cytokines, leading to epigenetic modification of the FOXP3 gene. Most of the understanding of the molecular events underlying tTreg generation is based on studies of murine models, whereas gaining similar insight in the human system has been very challenging. In this review, we will elucidate how inborn errors of immunity illuminate the critical non-redundant roles of certain molecules during tTreg development, shedding light on how their abnormal development and function cause well-defined diseases that manifest with autoimmunity alone or are associated with states of immune deficiency and autoinflammation.Keywords
Funding Information
- Lucile Packard Foundation for CHildren Health (NA)
This publication has 179 references indexed in Scilit:
- An evolutionarily conserved mutual interdependence between Aire and microRNAs in promiscuous gene expressionEuropean Journal of Immunology, 2013
- Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunityClinical Immunology, 2013
- Demethylation analysis of the FOXP3 locus shows quantitative defects of regulatory T cells in IPEX-like syndromeJournal of Autoimmunity, 2012
- Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactionsNature Medicine, 2011
- Secondary immunologic consequences in chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome)Clinical Immunology, 2010
- Thymus transplantationClinical Immunology, 2010
- Graft-versus-host diseaseThe Lancet, 2009
- Linked T Cell Receptor and Cytokine Signaling Govern the Development of the Regulatory T Cell RepertoireImmunity, 2008
- A Two-Step Process for Thymic Regulatory T Cell DevelopmentImmunity, 2008
- Regulatory T cell development in the absence of functional Foxp3Nature Immunology, 2007