01
X chromosome inactivation (XCI) is a critical mechanism in female mammals that ensures dosage compensation between the sexes by silencing one of the X chromosomes. In T cells, the XCI status is dynamically regulated and can be influenced by immune activation. However, the specific signaling requirements for XCI maintenance after T cell stimulation have remained unclear.
To explore this, the researchers first examined allele-specific gene expression and epigenomic profiles of the inactive X chromosome (Xi) in both unstimulated and activated T cells. They found that in unstimulated T cells, Xi is largely dosage compensated and enriched with repressive histone modifications like H3K27me3 but lacks others such as H2AK119-ubiquitin. Upon stimulating T cells via CD3 and CD28, the researchers observed the reappearance of H2AK119-ubiquitin at specific gene regions previously enriched with H3K27me3. Subsequently, they demonstrated that engagement of the T cell receptor (TCR) and activation of the NF-κB pathway are crucial for the localization of Xist RNA to the Xi.
Finally, using genetic models, chemical inhibitors, and samples from immunodeficient patients, the researchers confirmed that blocking NF-κB signaling disrupted the accumulation of Xist RNA at the Xi and altered the expression of X-linked genes. This suggests that the NF-κB pathway is a key player in the maintenance of XCI during T cell activation.
In conclusion, the study reveals a novel connection between immune signaling pathways and XCI regulation, highlighting the role of NF-κB in preserving XCI in activated T cells. This finding provides a deeper understanding of sex differences in immune responses and could inform therapies targeting immune regulation in females.
DOI: 10.1126/sciimmunol.ado0398
02
Dendritic cells are key antigen-presenting cells that transport tumor antigens from the tumor microenvironment (TME) to tumor-draining lymph nodes (tdLNs), where they activate T cells. Despite this known function, it remains unclear which specific DC subsets are responsible for these interactions and how they contribute to antitumor immunity and immunotherapy responses.
To address this, the researchers employed a proximity-based labeling technique called LIPSTIC (Labeling Immune Partnerships by SorTagging Intercellular Contacts). They used this method to trace DCs interacting with tumor-specific CD4+ T cells in the tdLN of mice bearing melanoma tumors. The results indicated that a small population of migratory DCs, rather than resident DCs, were responsible for presenting antigens to CD4+ T cells. These migratory DCs exhibited hyperactivated transcriptional profiles and were enriched for genes involved in antigen presentation and T cell activation. Furthermore, checkpoint blockade therapy using anti-CTLA-4 antibodies was shown to enhance these T cell–DC interactions, amplifying the antitumor response.
Additionally, the study’s single-cell transcriptomic analysis revealed that these LIPSTIC-labeled DCs shared transcriptional features with both cDC1 and cDC2 subsets but were predominantly found among cDC2 populations. The researchers confirmed that these DCs not only present antigens but also exhibit distinct gene signatures associated with cell migration and T cell interaction, emphasizing their specialized role in antitumor immunity.
In summary, this study highlights the importance of a specific subset of migratory DCs in coordinating CD4+ T cell responses against tumors. By identifying these hyperactivated DCs and demonstrating their enhancement by checkpoint blockade therapy, the research provides valuable insights into the mechanisms underlying effective antitumor immunity. This knowledge could inform strategies for optimizing cancer immunotherapies by targeting specific DC populations.
DOI: 10.1126/sciimmunol.adq8843
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Editor & Reviewer: Yanwen Zhu
