Aire in Autoimmunity

Abstract

The role of the autoimmune regulator (Aire) in central immune tolerance and thymic self-representation was first described more than 20 years ago, but fascinating new insights into its biology continue to emerge, particularly in the era of advanced single-cell genomics. We briefly describe the role of human genetics in the discovery of Aire, as well as insights into its function gained from genotype-phenotype correlations and the spectrum of Aire-associated autoimmunity-including insights from patients with Aire mutations with broad and diverse implications for human health. We then highlight emerging trends in Aire biology, focusing on three topic areas. First, we discuss medullary thymic epithelial diversity and the role of Aire in thymic epithelial development. Second, we highlight recent developments regarding the molecular mechanisms of Aire and its binding partners. Finally, we describe the rapidly evolving biology of the identity and function of extrathymic Aire-expressing cells (eTACs), and a novel eTAC subset called Janus cells, as well as their potential roles in immune homeostasis.

Keywords: Aire; Janus cells; autoimmunity; eTACs; immune tolerance; mimetic cells.

Figure 1

Domains and binding partners of Aire. (a) Schematic of the AIRE protein and its conserved domains. The human AIRE protein is 545 amino acids long and has five major conserved domains: CARD, SAND, PHD1, PRR, and PHD2. CARD is involved in the multimerization of AIRE, while PHD1 is a zinc-finger domain that has specificity for binding to and recognizing H3K4Me0 marks on chromatin (167). APS1 is classically autosomal recessive, and deleterious mutations are described across the length of the protein. Dominant mutations in AIRE can also occur through missense mutations downstream of CARD that cluster in the SAND domain and PHD1 and confer a hypomorphic effect on AIRE function. (b) Binding partners and molecular functions (and regulators) of the Aire complex, highlighting roles in histone binding and modification, transcriptional elongation and mRNA processing, and superenhancer binding and chromatin looping. Abbreviations: APS1, autoimmune polyglandular syndrome type 1; CARD, caspase recruitment domain; CBP, CREB-binding protein; NLS, nuclear localization sequence; P-TEFb, positive transcription elongation factor b; PHD, plant homeodomain; PRR, proline-rich region; SAND, Sp100, AIRE1, NucP41/75, DEAF1.

Figure 2

mTEC differentiation and relationship to Aire expression. (a) TEC development proceeds from multiple progenitor populations with varying commitment toward the mTEC lineage. Dominant Rank signaling induces the Aire⁺MHC-II^highCD80^high stage of development, characterized by high transcriptional complexity and a high capacity for antigen presentation. Within such cells, Aire-mediated transcriptional activation likely contributes to a metastable transitory state that amplifies access to multilineage epithelial differentiation. Possible mechanisms include direct effects on chromatin looping and remodeling, organization of or recruitment to functional nuclear compartments for transcription and mRNA splicing, and amplification of transcriptional noise. The expression of additional transcriptional regulators capable of binding closed chromatin (i.e., pioneer factors) is likely to be self-reinforcing and guide fate determination, together with local availability of extrinsic cues, such as cytokines and metabolic products. (b) Mimetic subsets and their relative abundance in scRNA-seq data sets. Lineage-defining transcription factors with orthogonal experimental evidence are shown in black font, and those proposed on the basis of bioinformatic analyses alone are shown in gray font. Abbreviations: mTEC, medullary thymic epithelial cell; scRNA-seq, single-cell RNA sequencing; TEC, thymic epithelial cell.

Figure 3

Identities and functions of eTACs. (a) Schematic illustration of overlap between eTACs (including Aire⁺ migratory DCs, JCs, and potentially additional populations present in early life; in various disease contexts; and in B cell lineages) and RORγt lineage APCs. The precise identities and lineage relationships between these populations remain largely undefined, though JCs are not precursors for most Aire⁺ migratory DCs. (b) Potential mechanism of RORγt⁺ Treg induction by RORγt lineage APCs, which depends on CCR7-mediated migration, MHC/TCR interactions, and activation of latent TGFB via cell surface integrin α_Vβ₈. Abbreviations: APC, antigen-presenting cell; DC, dendritic cell; eTAC, extrathymic Aire-expressing cell; JC, Janus cell; TC, Thetis cell; TCR, T cell receptor; Th17, T helper 17; Treg, regulatory T cell.