Extensive epigenetic reprogramming involves in memory CD8+ T-cell differentiation. The elaborate epigenetic rewiring underlying the heterogeneous functional states of CD8+ T cells remains hidden. Here, we profile single-cell chromatin accessibility and map enhancer-promoter interactomes to characterize the differentiation trajectory of memory CD8+ T cells. We reveal that under distinct epigenetic regulations, the early activated CD8+ T cells divergently originated for short-lived effector and memory precursor effector cells. We also uncover a defined epigenetic rewiring leading to the conversion from effector memory to central memory cells during memory formation. Additionally, we illustrate chromatin regulatory mechanisms underlying long-lasting versus transient transcription regulation during memory differentiation. Finally, we confirm the essential roles of Sox4 and Nrf2 in developing memory precursor effector and effector memory cells, respectively, and validate cell state-specific enhancers in regulating Il7r using CRISPR-Cas9. Our data pave the way for understanding the mechanism underlying epigenetic memory formation in CD8+ T-cell differentiation.
CD8-Positive T-Lymphocytes/metabolism* ; Cell Differentiation ; Chromatin/immunology* ; Animals ; Mice ; Immunologic Memory ; Epigenesis, Genetic ; SOXC Transcription Factors/immunology* ; NF-E2-Related Factor 2/immunology* ; Mice, Inbred C57BL ; Gene Regulatory Networks ; Enhancer Elements, Genetic

Objective To explore tumor control in triple-negative breast cancer(TNBC)through low-dose chemotherapy and anti-PD-L1 combination therapy.Methods 4T1 tumor-bearing mice were given either chemotherapy alone or combined with anti-PD-L1.The tumor growth and body weight of these mice were tracked,with immune profiles in the tumor microenvironment(TME)evaluated by flow cytometry.Results After single or combination use of carboplatin,cisplatin and paclitaxel in clinical dosage with or without anti-PD-L1,the body weight of 4T1-tumor bearing mice decreased rapidly and these mice were prone to death.Low-dose carboplatin had no effect on tumor control.Low-dose cisplatin and paclitaxel alone can delay the growth of 4T1,while low-dose cisplatin with anti-PD-L1 could enhance tumor control and increase the number and effector function of tumor-specific CD8+T cells.Conclusion Low-dose cisplatin with anti-PD-L1 presents a promising approach for TNBC control,which is attributed to the increase of tumor-specific CD8+T cells and enhanced effector function.

Objective To explore tumor control in triple-negative breast cancer(TNBC)through low-dose chemotherapy and anti-PD-L1 combination therapy.Methods 4T1 tumor-bearing mice were given either chemotherapy alone or combined with anti-PD-L1.The tumor growth and body weight of these mice were tracked,with immune profiles in the tumor microenvironment(TME)evaluated by flow cytometry.Results After single or combination use of carboplatin,cisplatin and paclitaxel in clinical dosage with or without anti-PD-L1,the body weight of 4T1-tumor bearing mice decreased rapidly and these mice were prone to death.Low-dose carboplatin had no effect on tumor control.Low-dose cisplatin and paclitaxel alone can delay the growth of 4T1,while low-dose cisplatin with anti-PD-L1 could enhance tumor control and increase the number and effector function of tumor-specific CD8+T cells.Conclusion Low-dose cisplatin with anti-PD-L1 presents a promising approach for TNBC control,which is attributed to the increase of tumor-specific CD8+T cells and enhanced effector function.

From January,2011 to December,2013,103 cases were selected from patients whose residual roots and crowns were restored by porcelain fusedto metal crowns after post core crown restorations.Patients were fully in-formed and randomly divided into two groups,including 51 cases receiving the post core restoration with dental root canal nail,52 cases being repaired with glass fiber post core restoration.After 6 ~12 months of follow-up observa-tion,in the group having received post core restoration with the dental root canal nail,there were 2 cases of crown root fracture,4 cases of falling off,the success rate was 88.24% (45 /51).In the group of fiber post and core res-toration,there was 1 case of crown root fracture,1 case of falling off;the success rate was 96.15% (50 /52).The restoration of fiber post core and porcelain fused to metal crown is the best choice of restoration of residual crown and root,but the root canal nail of teeth with light cured resin core is more economical,simple,easy to operate, and suitable for basic use.