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Central control of dynamic gene circuits governs T cell rest and activation
Arce MM. et al.
Nature. 2024
Cell-specific gene regulation in the immune system involves distinct IL-2 receptor (IL-2Rα) expression patterns in Treg and Teff cells. While Treg cells maintained high IL-2Rα expression, Teff cells transiently upregulated it upon activation. These differences informed therapeutic strategies targeting IL2RA to modulate immune responses.
Through CRISPR screens, researchers identified over 100 trans-regulators of IL-2Rα, uncovering cell-type- and stimulation-specific effects. Key findings included context-dependent regulators like GATA3, MED12, and BATF, which revealed distinct mechanisms in Treg and Teff cells under different conditions. These discoveries provided valuable insights into the dynamic regulation of IL-2Rα and its therapeutic potential.
Then, researchers validated cell-type-specific IL-2Rα regulators using CRISPR knockouts and Perturb-CITE-seq. This approach uncovered dynamic roles for factors like MED12 governing T cell activation and rest states. They identified hierarchical regulatory networks, where positive feedback loops maintained resting states, while activation required the repression of rest-promoting factors. MED12 emerged as a central player in both processes. Its knockout disrupted context-specific gene expression in CD4+ T cells, resulting in intermediate activation states and altered chromatin landscapes, including reduced enhancer activity at the IL2RA locus. By directing a network of cell-type- and state-specific regulators, MED12 shaped T cell identity and dynamic responses through chromatin modifications and interactions with Mediator subunits.
Furthermore, MED12 interacted with the COMPASS complex and influenced H3K4 methylation, RNA polymerase II pausing, and the transcription of key regulators such as KLF2 and MYC in human CD4+ T cells. It drove context-specific gene expression, establishing central governance over regulatory networks. These effects on resting and stimulated states were shown to be partially independent of Mediator kinases CDK8/CDK19.
Moreover, MED12 knockout enhanced the fitness of CAR-T cells by modulating activation-state transitions and reducing activation-induced cell death (AICD). Bulk RNA-seq and Perturb-seq analyses demonstrated reduced activation and apoptosis in MED12-targeted cells, which led to improved cell durability and expansion in stimulated conditions. These findings suggested that MED12 ablation might promote the therapeutic success of adoptive T cell therapies by striking a balance between activation and survival.
DOI: 10.1038/s41586-024-08314-y
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Chen KY. et al.
Cell. 2024
Inflamed lymph nodes during infection increase the likelihood of harboring lymphocytes specific to foreign antigens, thereby enhancing the immune response. The chemokine receptor CCR7, along with its ligands CCL19 and CCL21, plays a crucial role in naive lymphocyte entry into lymph nodes. However, the mechanism of lymphocyte recruitment when CCL21 expression is downregulated during inflammation remains unclear.
In various infection models, including systemic and local infections such as lymphocytic choriomeningitis virus (LCMV), CCL21 expression was downregulated. In inflamed lymph nodes (LNs), Ch25h, responsible for generating 7α,25-HC, was highly upregulated in high endothelial venules (HEVs) and stromal cells, while CCL21 and other chemokines like CXCL12 and CXCL13 were suppressed. This suggested that the Ch25h-oxysterol-EBI2 axis plays a pivotal role in naive lymphocyte recruitment during inflammation. Migration assays had shown that oxysterols, in combination with chemokines like CXCL12, enhanced integrin-dependent lymphocyte migration, indicating a cooperative mechanism. The suppression of CCL21 enhanced lymphocyte homing dependence on EBI2 during inflammation, a phenomenon that could be partially reversed by exogenous CCL19 but not CCL21, due to its limited mobility. This suppression was not driven by chromatin inaccessibility but might involve TGF-β signaling in fibroblastic reticular cells.
Endothelial Ch25h, expressed in HEVs, was critical for EBI2-mediated lymphocyte homing and lymph node enlargement during inflammation. Deleting Ch25h in endothelial cells reduced lymphocyte entry into draining LNs and diminished the CD4 T cell response, underlining its role in immune cell recruitment and activation. In addition to endothelial cells, radioresistant Langerhans cells (LCs) were a key source of Ch25h in inflamed lymph nodes, facilitating EBI2-dependent lymphocyte homing. LCs significantly upregulated Ch25h during inflammation, while conventional dendritic cells (cDCs) and radiosensitive cells contributed minimally to Ch25h production.
Similarly, tumor-draining lymph nodes (tdLNs) and inflamed peripheral tissues, such as tumors and skin, exhibited reduced CCL21 levels and increased reliance on EBI2-mediated oxysterol signaling for lymphocyte recruitment. In the subcutaneous MC38 tumor model, naive B cells entered into tdLNs and tumors were significantly EBI2-dependent, whereas CD8 T cells showed minimal reliance on EBI2, except for the CD8 Tcm subset, which exhibited modest dependence. Blocking or genetically deleting CCL19 increased reliance on EBI2 for lymphocyte homing, and the combined loss of EBI2-oxysterol and CCR7-CCL19 pathways resulted in drastically impaired lymphocyte entry into inflamed LNs.
DOI: 10.1016/j.cell.2024.11.031
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