Aire Gets Company for Immune Tolerance
2015; Cell Press; Volume: 163; Issue: 4 Linguagem: Inglês
10.1016/j.cell.2015.10.057
ISSN1097-4172
Autores Tópico(s)Diabetes and associated disorders
ResumoA specialized subset of epithelial cells in the thymus "promiscuously" transcribes thousands of peripheral genes to ensure that developing T cells can test their antigen receptors for dangerous autoreactivity. New findings by Takaba et al. indicate that the transcription factor Fezf2 acts independently of Aire in thymic epithelial cells to generate "genetic noise" for immunological tolerance. A specialized subset of epithelial cells in the thymus "promiscuously" transcribes thousands of peripheral genes to ensure that developing T cells can test their antigen receptors for dangerous autoreactivity. New findings by Takaba et al. indicate that the transcription factor Fezf2 acts independently of Aire in thymic epithelial cells to generate "genetic noise" for immunological tolerance. During T cell differentiation in the thymus, every T cell is equipped with a unique antigen receptor generated through somatic rearrangements. Whereas this vast T cell receptor repertoire confers protection against a universe of constantly evolving pathogens, the random nature of the rearrangement process inevitably leads to the emergence of potentially dangerous T cells that recognize the body's own structures. Prior to being released into the blood circulation, immature T cells must therefore "test" their antigen specificity on ligands within the thymic microenvironment and will undergo negative selection against autoreactivity. The scope of self-antigens that are visible to T cells for central tolerance is substantially broadened through the constitutive expression of a plethora of tissue restricted antigens (TRAs) by medullary thymic epithelial cells (mTECs) (Derbinski et al., 2001Derbinski J. Schulte A. Kyewski B. Klein L. Nat. Immunol. 2001; 2: 1032-1039Crossref PubMed Scopus (2) Google Scholar, Klein et al., 2014Klein L. Kyewski B. Allen P.M. Hogquist K.A. Nat. Rev. Immunol. 2014; 14: 377-391Crossref PubMed Scopus (784) Google Scholar). This phenomenon is referred to as "promiscuous gene expression," and it has evolved to facilitate T cell tolerance toward self-antigens that would otherwise be temporally or spatially secluded from the immune system. In this issue of Cell, Takaba et al. (2015) identify the transcription factor Fezf2 as a key driver of promiscuous gene expression in mTECs, essential to prevent spontaneous autoimmunity against multiple tissues (Takaba et al., 2015Takaba H. Morishita Y. Tomofuji Y. Danks L. Nitta T. Komatsu N. Kodama T. Takayanagi H. Cell. 2015; 163 (this issue): 975-987Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar). Tightly controlled expression of cell-type-specific genetic programs is indispensable for tissue identity and homeostasis, and multiple layers of control act in concert to prevent ectopic gene expression. How do mTECs deliberately violate these rules in order to generate "beneficial genetic noise"? A breakthrough in the field emerged from studies on the autoimmune polyendocrine syndrome (APS), a monogenically inherited human autoimmune disease resulting from mutations in the autoimmune regulator (Aire) gene. In mice, Aire was found to be essential for "ectopic" TRA expression in mTECs, and knockout of Aire recapitulated several aspects of APS (Anderson et al., 2002Anderson M.S. Venanzi E.S. Klein L. Chen Z. Berzins S.P. Turley S.J. von Boehmer H. Bronson R. Dierich A. Benoist C. Mathis D. Science. 2002; 298: 1395-1401Crossref PubMed Scopus (1866) Google Scholar). Strikingly, however, it turned out that promiscuous gene expression was not fully abolished in the absence of Aire (Derbinski et al., 2005Derbinski J. Gäbler J. Brors B. Tierling S. Jonnakuty S. Hergenhahn M. Peltonen L. Walter J. Kyewski B. J. Exp. Med. 2005; 202: 33-45Crossref PubMed Scopus (438) Google Scholar), suggesting the existence of additional transcriptional regulators. Still, most research in the field focused on deciphering the molecular workings of Aire (Mathis and Benoist, 2009Mathis D. Benoist C. Annu. Rev. Immunol. 2009; 27: 287-312Crossref PubMed Scopus (474) Google Scholar, Peterson et al., 2008Peterson P. Org T. Rebane A. Nat. Rev. Immunol. 2008; 8: 948-957Crossref PubMed Scopus (183) Google Scholar), while largely ignoring how Aire-independent promiscuous gene expression is regulated. Here, Takaba et al., 2015Takaba H. Morishita Y. Tomofuji Y. Danks L. Nitta T. Komatsu N. Kodama T. Takayanagi H. Cell. 2015; 163 (this issue): 975-987Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar hypothesize that any Aire-independent additional regulators of promiscuous gene expression should be differentially expressed between mTECs and their nearest neighbor, the cortical thymic epithelial cells (cTECs), who share a common precursor with mTECs but do not express TRAs. Among the genes that were differentially expressed in mTECs versus cTECs, they find the transcriptional regulator Fezf2 (forebrain expressed zinc finger 2) to be expressed in mTECs, but not in other thymic stromal cell types. Previous work has implicated Fezf2 in corticospinal motor neuron differentiation, and Fezf2-deficient mice do not survive beyond weaning, explaining why a potential role of Fezf2 in the immune system may have gone unnoticed. By comparing gene expression profiles, Takaba et al., 2015Takaba H. Morishita Y. Tomofuji Y. Danks L. Nitta T. Komatsu N. Kodama T. Takayanagi H. Cell. 2015; 163 (this issue): 975-987Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar demonstrate that numerous TRA transcripts are downregulated in Fezf2-deficient mTECs. Importantly, the majority of these Fezf2-dependent TRAs are not affected in Aire-deficient mTECs, and most Aire-dependent TRAs remain expressed in the absence of Fezf2, strongly supporting an Aire-independent and non-redundant role of Fezf2 in the promotion of promiscuous gene expression. Along these lines, the authors go on to show that Fezf2 deficiency in thymic epithelium elicits a spectrum of autoimmune manifestations that is partly distinct from those seen in Aire-deficient mice. Remarkably, several aspects of Fezf2's role in the thymus seem to follow a fundamentally different biological and mechanistic logic as compared to what is known about Aire (Figure 1). First, Aire's function as a "transcriptional randomizer" is likely to have evolved simultaneous to, and as a consequence of, the emergence of adaptive T-cell-mediated immunity in jawed vertebrates some 500 million years ago (Saltis et al., 2008Saltis M. Criscitiello M.F. Ohta Y. Keefe M. Trede N.S. Goitsuka R. Flajnik M.F. Immunogenetics. 2008; 60: 105-114Crossref PubMed Scopus (40) Google Scholar). By contrast, Fezf2's evolutionary conserved primary function seems to be that of a master regulator of cell fate specification in corticospinal motor neurons. Thus, Aire appears to be a genuine "tolerance gene," whereas Fezf2 instead might exemplify the evolutionary co-optation of a neuronal gene in a distinct cellular and functional context. Second, Aire lacks a DNA-binding domain and seems to seek out its targets through binding inactive chromatin marks prior to recruiting factors that facilitate "illegitimate" transcription by generating double-strand breaks, fostering mRNA processing, and releasing stalled RNA Polymerase (Mathis and Benoist, 2009Mathis D. Benoist C. Annu. Rev. Immunol. 2009; 27: 287-312Crossref PubMed Scopus (474) Google Scholar, Peterson et al., 2008Peterson P. Org T. Rebane A. Nat. Rev. Immunol. 2008; 8: 948-957Crossref PubMed Scopus (183) Google Scholar). By contrast, Fezf2 is a "bona fide" transcription factor that directly binds to target DNA. In neuronal progenitors, Fezf2 binds in the vicinity of the transcriptional start site of more than 10,000 genes (Lodato et al., 2014Lodato S. Molyneaux B.J. Zuccaro E. Goff L.A. Chen H.H. Yuan W. Meleski A. Takahashi E. Mahony S. Rinn J.L. et al.Nat. Neurosci. 2014; 17: 1046-1054Crossref PubMed Scopus (77) Google Scholar), which has obvious implications for the spectrum of genes that might be controlled by Fezf2 in mTECs. Finally, whereas Aire expression in mTECs is regulated by the TNF superfamily members RANK and CD40, Takaba et al., 2015Takaba H. Morishita Y. Tomofuji Y. Danks L. Nitta T. Komatsu N. Kodama T. Takayanagi H. Cell. 2015; 163 (this issue): 975-987Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar show that the expression of Fezf2 critically depends upon the lymphotoxin (LT) β signaling axis. Taken together, the work by Takaba et al., 2015Takaba H. Morishita Y. Tomofuji Y. Danks L. Nitta T. Komatsu N. Kodama T. Takayanagi H. Cell. 2015; 163 (this issue): 975-987Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar represents a major step forward in our understanding of how promiscuous gene expression in mTECs is brought about and how it safeguards against autoimmunity. At the same time, these exciting new insights raise a number of questions: do the altered 3D organization of the thymic medulla and subtle alterations in the ratio of mTEC subsets in Fezf2–/– mice contribute to faulty T cell selection independent of Fezf2's role in promiscuous gene expression? Given the perplexing observation that individual mTECs only express a subset of Aire-dependent TRAs, does the same apply to Fezf2-dependent transcripts? Does Fezf2 similarly promote promiscuous gene expression in the human thymus, and if so, are mutations or allelic variants of Fezf2 associated with human autoimmune diseases? And finally, does the complementary action of Aire and Fezf2 account for the full extent of promiscuous gene expression in mTECs, or are as-yet-unknown, additional, and independent factors involved? Fezf2 Orchestrates a Thymic Program of Self-Antigen Expression for Immune ToleranceTakaba et al.CellNovember 05, 2015In BriefTo promote immunological tolerance of one's own proteins, the protein Fezf2 directly regulates transcription of tissue-restricted antigen genes in in the thymus, where it functions independently and via a distinct pathway from Aire, the transcriptional regulator widely thought to be primarily responsible for self-tolerance. Full-Text PDF Open Archive
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