Thymic epithelial cells (TEC) play an indispensable role in the development and selection of immunocompetent, yet self-tolerant T cells. To provide further insights into TEC functional and developmental diversity, we utilized multiome analysis, which revealed a detailed atlas of the TEC compartment based on their transcriptional states and chromatin landscapes. The analysis also highlighted numerous unconventional TEC subsets, which shared striking similarities with functionally well-defined parenchymal populations, including endocrine cells, microfold cells or myocytes. Moreover, our fate mapping experiments revealed that most of these rare TEC “parenchymal analogues” differentiated from Csnb+ MHCIIhi mTEC precursors, with varying impacts of Aire on their development. By further focusing on the endocrine- and the microfold-TEC populations, we found that both subsets play different and non-redundant functional roles and require different transcription factors for their terminal differentiation. Specifically, while the endocrine-TEC required Insm1 for their development, and were critical for induction of self-tolerance to various endocrine tissues, the microfold-TEC required Spib for their development, and were essential for the generation of thymic IgA+ plasma cells. Collectively, our study reveals that MHCIIhi mTEC have the potential to differentiate into various types of molecularly functionally defined cells, which not only contribute to the induction of central tolerance, but also regulate homeostasis of other thymus-resident populations.
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Background and Aims
Crohn’s disease is a debilitating chronic inflammatory disorder of the mammalian gastrointestinal tract. Current interventions using anti-TNF biologics show long term benefit in only half of patients. This study focused on the role of the TNF receptor 1 (TNFR1) in pathogenesis in a TNF-driven model of ileitis.
Methods
We studied TNF ΔAU-rich element (ARE)/+ (TNFdARE) mice, which develop progressive ileitis similar to Crohn’s ileitis. Histopathological analysis and gene expression profiling were used to characterize disease progression from 5 to 16 weeks. Mice with TNFR1 hemizygosity (TNFdARE/R1het) allowed us to assess gene dosage effects. Transcriptional profiling established inflection points in disease progression; inflammatory gene expression increased at 8 weeks with a plateau by 10 weeks, so these were selected as end points of treatment using the TNF biologic Infliximab and the TNFR1-specific XPro1595. Differences in recruitment of cells in the lamina propria were assessed using flow cytometry.
Results
TNFdARE/R1het mice displayed stable long term protection from disease, associated with decreased recruitment of CD11b hiF4/80lo monocytes and CD11b hiLy6Ghi neutrophils, suggesting an important role of TNFR1 signaling in pathogenesis, and indicating potential benefit from TNFR1-specific intervention. Treatment with Infliximab and XPro1595 both showed similar impact on disease in TNFdARE mice. Importantly, these beneficial effects were greatly surpassed by hemizygosity at the TNFR1 locus.
Conclusions
Treatment with either Infliximab or XPro1595 produced moderate protection from ileitis in TNFdARE mice. However, hemizygosity at the TNFR1 locus in TNFdARE mice showed far better protection, implicating TNFR1 signaling as a key mediator of TNF-driven disease.
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