Regulatory T (Treg) cells are known to impede antitumor immunity, yet the regulatory mechanisms and functional roles of these cells remain poorly understood. In this study, through the characterization of multiple cancer models, we identified a substantial presence of peripherally induced Treg cells in the tumor microenvironment (TME). Depletion of these cells triggered antitumor responses and provided potent therapeutic effects by increasing functional CD8+ T cells. Fate-mapping and transfer experiments revealed that IFN-γ–expressing T helper (Th) 1 cells differentiated into Treg cells in response to TGF-β signaling in tumors. Pseudotime trajectory analysis further revealed the terminal differentiation of Th1-like Treg cells from Th1 cells in the TME. Tumor-resident Treg cells highly expressed T-bet, which was essential for their functions in the TME. Additionally, CD39 was highly expressed by T-bet+ Treg cells in both mouse and human tumors, and was necessary for Treg cell-mediated suppression of CD8+ T cell responses. Our study elucidated the developmental pathway of intratumoral Treg cells and highlighted novel strategies for targeting them in cancer patients.

Innate lymphoid cells (ILC) are similar to T helper (Th) cells in expression of cytokines and transcription factors. For example, RORγt is the lineage-specific transcription factor for both ILC3 and Th17 cells. However, the ILC counterpart for BCL6-expressing T follicular helper (Tfh) cells has not been defined. Here, we report that in the ILC compartment, BCL6 is selectively co-expressed with not only CXCR5 but also RORγt and CCR6 in ILC3 from multiple tissues. BCL6-deficient ILC3 produces enhanced levels of IL-17A and IL-22. More importantly, phenotypic and single-cell ATAC-seq analysis show that absence of BCL6 in mature ILC3 increases the numbers of ILC1 and transitional cells co-expressing ILC3 and ILC1 marker genes. A lineage-tracing experiment further reveals BCL6+ ILC3 to ILC1 trans-differentiation under steady state. Finally, microbiota promote BCL6 expression in colonic CCR6+ ILC3 and thus reinforce their stability. Collectively, our data have demonstrated that CCR6+ ILC3 have both Th17 and Tfh programs and that BCL6 expression in these cells functions to maintain their lineage identity.

Coronary atherosclerosis is one of the major factors causing cardiovascular diseases. However, identifying the tipping point (predisease state of disease) and detecting early-warning signals of human coronary atherosclerosis for individual patients are still great challenges. The landscape dynamic network biomarkers (l-DNB) methodology is based on the theory of dynamic network biomarkers (DNBs), and can use only one-sample omics data to identify the tipping point of complex diseases, such as coronary atherosclerosis. Based on the l-DNB methodology, by using the metabolomics data of plasma of patients with coronary atherosclerosis at different stages, we accurately detected the early-warning signals of each patient. Moreover, we also discovered a group of dynamic network biomarkers (DNBs) which play key roles in driving the progression of the disease. Our study provides a new insight into the individualized early diagnosis of coronary atherosclerosis and may contribute to the development of personalized medicine.

The airway epithelium plays a crucial role in maintaining lung homeostasis, and its dysregulation is often linked to various lung diseases, including asthma. Ciliated cells, abundantly present in the mammalian airway epithelium, have a critical function in clearing inhaled particles and pathogens. We show here that ciliated cells constitutively express IL-17D, which functions as an immune brake in limiting allergic inflammation in murine models of asthma. Mechanistically, IL-17D functions to prevent influx of classical monocytes into the lung and their subsequent conversion to pathogenic alveolar macrophages, through binding to CD93. Deficiency in Il17d or Cd93 increased the expression of chemokine receptors on classical monocytes, including CCR6, thereby enhancing their recruitment to the lung and type 2 inflammation. Our study thus reveals an unexpected protective role of ciliated cells and IL-17D in lung immune responses and asthma, which can be further explored for treating related diseases.

Retinoic acid receptor–related orphan receptor γt (RORγt) is the master transcription factor for type 17 immune cells, including T helper 17 (T _H 17) cells, group 3 innate lymphoid cells (ILC3s), RORγt ⁺ regulatory T (T _reg ) cells, and RORγt ⁺ γδT cells. While trans-regulatory mechanisms governing Rorc expression are well characterized, cis-regulatory mechanisms, particularly in innate lymphocytes, remain partially understood. Here, we identify CNS11 as an essential cis-regulatory element of Rorc . In T _H 17 cells, CNS11 was dispensable for induction but critical for maintaining RORγt expression. In contrast, CNS11 deletion blocked ILC3 progenitor induction, abolishing secondary lymphoid organ formation. CNS11 deletion also abolished the development of RORγt ⁺ T _reg , RORγt ⁺ γδT, and RORγt ⁺ antigen-presenting cells. Mechanistically, CNS11 functioned through a RORγt-dependent feed-forward loop with cell type–specific cofactors: cooperating with RORγt and runt-related transcription factor 3 to direct ILC3 development and with RORγt and/or c-MAF to sustain RORγt expression in T _H 17, RORγt ⁺ T _reg , and RORγt ⁺ γδT cells. Our study reveals CNS11 as a key transcription factor binding hub and master control region for Rorc transcription in distinct lymphocytes.