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.
Background: A high incidence of asthma is prevalent among residents near the Salton Sea, a large inland terminal lake in southern California. This arid region has high levels of ambient particulate matter (PM); yet while high PM levels are often associated with asthma in many environments, it is possible that the rapidly retreating lake may contribute components with a specific role in promoting asthma symptoms.
Objectives: Our hypothesis is that asthma may be higher in residents closest to the Salton Sea due to chronic exposures to playa dust. Playa emissions may be concentrating dissolved material from the lake, with microbial components capable of inducing pulmonary innate immune responses. Such inflammatory responses may contribute to the development of asthma-like symptoms in residents. To test this hypothesis, we used a mouse model of aerosol exposures to assess the effects of playa dust.
Methods: From dust collected around the Salton Sea region, aqueous extracts were used to generate aerosols, which were injected into an environmental chamber for mouse exposure studies. We compared the effects of exposure to Salton Sea aerosols, as well as to known immunostimulatory reference materials. Acute 48-hour and chronic 7-day exposures were compared, with lungs analyzed for inflammatory cell recruitment and gene expression.
Results: Dust from sites nearest to the Salton Sea triggered lung neutrophil inflammation that was stronger at 48-hours but reduced at 7-days. This acute inflammatory profile and kinetics resembled the response to innate immune ligands LTA and LPS while distinct from the classic allergic response to Alternaria.
Conclusion: Lung inflammatory responses to Salton Sea dusts are similar to acute innate immune responses, raising the possibility that microbial components are entrained in the dust, promoting inflammation. This effect highlights the health risks at drying terminal lakes from inflammatory components in dust emissions from exposed lakebed.
El Population Council realiza investigación en todo el mundo con el fin de mejorar políticas, programas y productos en tres áreas: VIH y SIDA; pobreza, género y juventud; y salud reproductiva.
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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