Project description:Tumor microenvironment (TME) plays critical roles in both tumor progression and immunotherapeutic efficacy. Here using single-cell RNA sequencing (scRNA-seq), we described the TME heterogeneity and found a specific state of CCL22+ dendritic cell (mregDC) cross talk close to regulatory T cells (Treg). We analyzed cell–cell communication mediated by ligand–receptor interactions and finally found that mregDCs probably attract Treg cells via chemotaxis and physically interact with them in tumor. Within this cross talk, Treg cells received activation signals from mregDCs and upregulated suppressive and adhesion molecules, including PD-1, ICOS, CTLA-4 and OX-40, further enhancing their interaction with mregDCs. In turn, the association of Treg cells with mregDCs restrained the trafficking of tumor antigen-bearing dendritic cells to draining mesenteric lymph nodes and thus dampened the presentation of tumor antigens to initiate anti-tumor immune responses in a cell contact dependent manner.
Project description:To investigate the mechanism by which Treg cell positioning is regulated in our manuscript,we performed RNAseq on tumor Treg cells from Apc Min/+ Foxp3 DTR mice versus normal colonic Treg cells from Foxp3 DTR mice.
Project description:To investigate the clonality of tumor Treg cells, we performed TCRseq on tumor Treg cells from Apc Min/+ mice versus normal colonic Treg cells from WT mice.
Project description:Failed clearance of apoptotic cells drives pathogen persistence, tissue damage, and damage associated molecular patterns accumulation, fueling immune remodeling. Despite its pathophysiological significance, the precise immunometabolic reprogramming underlying impaired phagocytic signaling in macrophages remains poorly defined. Here, we reveal a correlation between Crohn’s disease (CD) activity and MERTK⁺ macrophage abundance, establishing a previously unrecognized link between MERTK signaling and the orchestrated regulation of mitochondrial bioenergetics and cholesterol homeostasis. MERTK deficiency activates cholesterol biosynthesis in the endoplasmic reticulum (ER) and disrupts the protein degradation of the cholesterol transporter GRAM Domain Containing 1A (GRAMD1A) localized to the ER. Combined live-cell imaging and metabolomics show enhanced ER-to-mitochondria cholesterol trafficking, oxysterol accumulation, and impaired oxidative phosphorylation. Critically, this mitochondrial dysfunction activates innate immune signaling cascades by releasing mtDNA and dsRNA. Our findings define an elegant mechanistic axis linking defective efferocytosis to metabolic reprogramming and inflammatory disease pathogenesis.