Aire is a transcriptional regulator that controls immunological tolerance by driving the expression of a large repertoire of gene transcripts encoding peripheral-tissue self-antigens in thymic medullary epithelial cells (MECs). Thereby, it promotes both the negative selection of effector T cells capable of recognizing these self- antigens and positive selection of regulatory T cells that can rein in the effectors. Mutations in the AIRE gene underlie a rare multi-organ autoimmune disease called APECED or APS-1, and abnormalities in the Aire pathway, reflecting polymorphisms in either Aire target-loci or in the AIRE gene itself, have also been implicated in certain of the more common autoimmune disorders, notably type-1 diabetes, myasthenia gravis, vitiligo and pernicious anemia. The studies proposed herein issue from our surprising finding that Aire's impact on immunological tolerance has a strikingly narrow temporal window: its expression during the perinatal period is necessary and sufficient to avoid the multi-organ autoimmune disease typical of Aire-knockout mice. Hence, this project's overall goal is to understand why Aire must be expressed in perinatal mice to guard against autoimmunity, but is dispensable in adults.
Its Specific Aims are to: 1. evaluate the role of DM and DO in the selection of Foxp3+CD4+ Treg cells; 2. explore the fate of perinatally generated Tregs; and 3. compare perinatal and adult CD4+ Teff cells and Aire's impact thereon. Addressing these Aims will entail the generation of new lines of multi-engineered mice, tailored to highlight the impact of designated molecules (e.g. Aire, DM) or cell-types (e.g. ?:? T cells); as well as state-of-the-art approaches to the genomic analysis of ultra small immunocyte populations. Results from these studies will not only elucidate mechanisms underlying the temporal window of Aire's impact on immunological tolerance but, more generally, should yield new insights into the molecular and cellular underpinnings of neonatal tolerance, a phenomenon that has fascinated immunologists for decades. Autoimmune diseases afflict 7-10% of Americans, and are rising in incidence. It is imperative to learn how to re-establish immunological tolerance in individuals with autoimmune disorders - understanding tolerance mechanisms will undoubtedly advance this goal.
This study focuses on the mechanisms of action of Aire, the protein encoded by the gene mutated in individuals with APECED (or APS-1), a primary immunodeficiency disease characterized by multi-organ autoimmunity. While APECED patients are rather rare, the Aire pathway - via polymorphisms in either Aire target-loci or in the gene encoding Aire itself - have been implicated in several of the more common autoimmune disorders, including type-1 diabetes, myasthenia gravis, vitiligo and pernicious anemia. Targeting of new cellular and molecular interactions and pathways highlighted in this study may have therapeutic potential; in addition, we should learn about the optimum points for intervening in autoimmune disease course.
|Bansal, Kushagra; Yoshida, Hideyuki; Benoist, Christophe et al. (2017) The transcriptional regulator Aire binds to and activates super-enhancers. Nat Immunol 18:263-273|
|Mathis, Diane; Benoist, Christophe (2016) Promiscuity Promotes Tolerance. J Immunol 196:2913-4|
|Fujikado, Noriyuki; Mann, Alexander O; Bansal, Kushagra et al. (2016) Aire Inhibits the Generation of a Perinatal Population of Interleukin-17A-Producing ?? T Cells to Promote Immunologic Tolerance. Immunity 45:999-1012|
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|Yoshida, Hideyuki; Bansal, Kushagra; Schaefer, Uwe et al. (2015) Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells. Proc Natl Acad Sci U S A 112:E4448-57|
|Meredith, Matthew; Zemmour, David; Mathis, Diane et al. (2015) Aire controls gene expression in the thymic epithelium with ordered stochasticity. Nat Immunol 16:942-9|
|Giraud, Matthieu; Jmari, Nada; Du, Lina et al. (2014) An RNAi screen for Aire cofactors reveals a role for Hnrnpl in polymerase release and Aire-activated ectopic transcription. Proc Natl Acad Sci U S A 111:1491-6|
|Giraud, Matthieu; Yoshida, Hideyuki; Abramson, Jakub et al. (2012) Aire unleashes stalled RNA polymerase to induce ectopic gene expression in thymic epithelial cells. Proc Natl Acad Sci U S A 109:535-40|
|Mathis, Diane; Benoist, Christophe (2010) Levees of immunological tolerance. Nat Immunol 11:3-6|
|Koh, Andrew S; Kingston, Robert E; Benoist, Christophe et al. (2010) Global relevance of Aire binding to hypomethylated lysine-4 of histone-3. Proc Natl Acad Sci U S A 107:13016-21|
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