Aire is a transcriptional regulator that induces the promiscuous expression of thousands of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs), a step critical for the induction of immunological self-tolerance. Studies have offered molecular insights into how Aire operates, but more comprehensive understanding of this process still remains elusive. Here we found abundant expression of the protein deacetylase Sirtuin-1 (Sirt1) in mature Aire(+) mTECs, wherein it was required for the expression of Aire-dependent TRA-encoding genes and the subsequent induction of immunological self-tolerance. Our study elucidates a previously unknown molecular mechanism for Aire-mediated transcriptional regulation and identifies a unique function for Sirt1 in preventing organ-specific autoimmunity.

The autoimmune regulator (AIRE) is essential for the establishment of central tolerance and prevention of autoimmunity. Interestingly, different AIRE mutations cause autoimmunity in either recessive or dominant-negative manners. Using engineered mouse models, we establish that some monoallelic mutants, including C311Y and C446G, cause breakdown of central tolerance. By using RNAseq, ATACseq, ChIPseq, and protein analyses, we dissect the underlying mechanisms for their dominancy. Specifically, we show that recessive mutations result in a lack of AIRE protein expression, while the dominant mutations in both PHD domains augment the expression of dysfunctional AIRE with altered capacity to bind chromatin and induce gene expression. Finally, we demonstrate that enhanced AIRE expression is partially due to increased chromatin accessibility of the AIRE proximal enhancer, which serves as a docking site for AIRE binding. Therefore, our data not only elucidate why some AIRE mutations are recessive while others dominant, but also identify an autoregulatory mechanism by which AIRE negatively modulates its own expression.

In spite of recent advances in proteomics, quantitative analyses of protein-protein interactions (PPIs) or post-translational modifications (PTMs) in rare cell populations remain challenging. This is in particular true for analyses of rare immune and/or stem cell populations that are directly isolated from humans or animal models, and which are often characterized by multiple surface markers. To overcome these limitations, here we have developed proximity ligation imaging cytometry (PLIC), a protocol for proteomic analysis of rare cells. Specifically, by employing PLIC on medullary thymic epithelial cells (mTECs), which serve as a paradigm for a rare immune population, we demonstrate that PLIC overcomes the inherent limitations of conventional proteomic approaches and enables a high-resolution detection and quantification of PPIs and PTMs at a single cell level.

Introduction Women’s olfactory perception varies across the menstrual cycle. The influence of oral contraceptives on this variability remains unclear. Methods To further estimate this, we assessed discrimination performance for both body odors and ordinary odorants in 36 women, 18 naturally ovulating, and 18 using oral contraceptives. Each participant was tested once a week over the course of a month, and data was then parsed into menstrual phases. Results In naturally ovulating women, at the transition from follicular to luteal phases, there was a decline of 19% ( p = 0.003) in olfactory discrimination of body odors but not ordinary odorants. In turn, in women using oral contraceptives, only at a later time of the month, at a point corresponding to the late luteal phase and shift from post-ovulation to pre-menstruation, was there a decline of 20% ( p = 0.002) in olfactory discrimination performance. Moreover, when we reorganized the data from women using oral contraceptives in order to separately assess the contraceptive withdrawal period (the few days off pills), we observed a 23% reduction ( p = 0.01) in discrimination accuracy of body odors but not ordinary odorants during this time alone. Conclusions Women have reduced ability to discriminate body odors during the withdrawal period of oral contraception. Implications If women indeed consider men’s body odor in their mate selections, then the oral contraception withdrawal period may not be the best time to make such decisions.

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