Genetically targeting the BATF family transcription factors BATF and BATF3 in the mouse abrogates effector T cell activities and enables long-term heart allograft survival

Wang, Yixuan; Xiao, Xiang; Kong, Gangcheng; Wen, Mou; Wang, Guangchuan; Ghobrial, Rafik M.; Dong, Nianguo; Chen, Wenhao; Li, Xian Chang

doi:10.1111/ajt.16861

Cited by 10 publications

(7 citation statements)

References 30 publications

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“…In the setting of infections, the impaired effector differentiation and function of BATF-deficient CD8 + T cells eventually results in the defeats to eliminate lymphocytic choriomeningitis virus (LCMV) infections ( 24 , 31 , 32 ). The requirement of BATF family transcription factors in effector differentiation is also demonstrated in other settings ( 40 – 42 ). Consistent with these findings, our data showed that BATF-deficient CD8 + T cells exhibited a compromised effector phenotype and lost the capacity to mediate transplant rejection.…”

Section: Discussionmentioning

confidence: 69%

Ablation of BATF Alleviates Transplant Rejection via Abrogating the Effector Differentiation and Memory Responses of CD8+ T Cells

Zou

Chen

et al. 2022

Front. Immunol.

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Allogeneic CD8+ T cells are prominently involved in allograft rejection, but how their effector differentiation and function are regulated at a transcriptional level is not fully understood. Herein, we identified the basic leucine zipper ATF-like transcription factor (BATF) as a key transcription factor that drives the effector program of allogeneic CD8+ T cells. We found that BATF is highly expressed in graft-infiltrating CD8+ T cells, and its ablation in CD8+ T cells significantly prolonged skin allograft survival in a fully MHC-mismatched transplantation model. To investigate how BATF dictates allogeneic CD8+ T cell response, BATF–/– and wild-type (WT) CD8+ T cells were mixed in a 1:1 ratio and adoptively transferred into B6.Rag1–/– mice 1 day prior to skin transplantation. Compared with WT CD8+ T cells at the peak of rejection response, BATF–/– CD8+ T cells displayed a dysfunctional phenotype, evident by their failure to differentiate into CD127–KLRG1+ terminal effectors, impaired proliferative capacity and production of pro-inflammatory cytokines/cytotoxic molecules, and diminished capacity to infiltrate allografts. In association with the failure of effector differentiation, BATF–/– CD8+ T cells largely retained TCF1 expression and expressed significantly low levels of T-bet, TOX, and Ki67. At the memory phase, BATF-deficient CD8+ T cells displayed impaired effector differentiation upon allogeneic antigen re-stimulation. Therefore, BATF is a critical transcriptional determinant that governs the terminal differentiation and memory responses of allogeneic CD8+ T cells in the transplantation setting. Targeting BATF in CD8+ T cells may be an attractive therapeutic approach to promote transplant acceptance.

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Section: Discussionmentioning

confidence: 69%

Ablation of BATF Alleviates Transplant Rejection via Abrogating the Effector Differentiation and Memory Responses of CD8+ T Cells

Zou

Chen

et al. 2022

Front. Immunol.

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“…One studies have shown that after in vitro and in vivo injection of endotoxin and LPS, six candidate genes(BATF, BID, C3aR1, IL1RN, SEC61B and SLC43A3) were identi ed to be associated with in ammation and atherosclerosis [28] . Another study demonstrate that the BATF and BATF3 are critical regulators of T effector functions, thus making them attractive targets for therapeutic interventions in heart allograft [29] . Our Xcell results showed that the number of macrophages in unstable plates increased signi cantly, indicating that the number and function of macrophages play a very important role in the progression of plaques, above studies indicate that BATF is mainly involved in the progression of cardiovascular disease as a regulatory factor of T cells, a single-cell sequencing database analysis showed that (https://panglaodb.se/index.html) BATF was also highly expressed in macrophages, so, it may be involved in regulating plaque instability or rupture.…”

Section: Discussionmentioning

confidence: 99%

The underlying molecular mechanisms and biomarkers of plaque vulnerability based on bioinformatics analysis

Cheng

Yang

et al. 2022

Preprint

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Aim：The study aimed to identify the underlying differentially expressed genes (DEGs) and mechanism of unstable atherosclerotic plaque using bioinformatics methods.Methods: GSE120521, which includes four unstable samples and four stable atherosclerotic samples, was downloaded from the GEO database. DEGs were identified using LIMMA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of DEGs were performed using the Database for metascape Visualization online tool. Based on the STRING database, protein-protein interactions (PPIs) network among DEGs were constructed. Regulatory networks were visualized using Cytoscape. we use the xCell to analyze the different immune cell subtypes.Result： A total of 1626 DEGs (1034 up-regulated and 592 down-regulated DEGs) were identified between unstable and stable samples. I pulled 62 transcription factors (34 up-regulated TFs and 28 down-regulated TFs) from the Trust database. The up regulated TFs were mainly enrichment in positive regulation of myeloid leukocyte differentiation, and the downregulated TFs were mainly enrichment in connective tissue development. In the PPI network, RB1，CEBPA，PPARG，BATF was the most significantly up-regulated gene in ruptured atherosclerotic samples. The immune cell composition enriched in CD cells and macrophages in the unstable carotid plaque.Conclusions: up-regulated RB1，CEBPA，PPARG，BATF and Down-regulated SRF，MYOCD，HEY2，GATA6 might perform critical promotional roles in atherosclerotic plaque rupture, furthermore, Number and polarization of macrophages may play an important role in vulnerable plaques.

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“…One studies have shown that after in vitro and in vivo injection of endotoxin and LPS, six candidate genes (BATF, BID, C3aR1, IL1RN, SEC61B and SLC43A3) were identified to be associated with inflammation and atherosclerosis [28]. Another study demonstrate that the BATF and BATF3 are critical regulators of T effector functions, thus making them attractive targets for therapeutic interventions in heart allograft [29]. Our xCell results showed that the number of macrophages in unstable plates increased significantly, indicating that the number and function of macrophages play a very important role in the progression of plaques, above studies indicate that BATF is mainly involved in the progression of cardiovascular disease as a regulatory factor of T cells, a single-cell sequencing database analysis showed that (https:// pangl aodb.…”

Section: Discussionmentioning

confidence: 99%

The underlying molecular mechanisms and biomarkers of plaque vulnerability based on bioinformatics analysis

Cheng

Yang

et al. 2022

Eur J Med Res

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Aim The study aimed to identify the underlying differentially expressed genes (DEGs) and mechanism of unstable atherosclerotic plaque using bioinformatics methods. Methods GSE120521, which includes four unstable samples and four stable atherosclerotic samples, was downloaded from the GEO database. DEGs were identified using LIMMA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of DEGs were performed using the Database for metascape Visualization online tool. Based on the STRING database, protein–protein interactions (PPIs) network among DEGs were constructed. Regulatory networks were visualized using Cytoscape. We use the xCell to analyze the different immune cell subtypes. Results A total of 1626 DEGs (1034 up-regulated and 592 down-regulated DEGs) were identified between unstable and stable samples. I pulled 62 transcription factors (34 up-regulated TFs and 28 down-regulated TFs) from the Trust database. The up-regulated TFs were mainly enrichment in positive regulation of myeloid leukocyte differentiation, and the down-regulated TFs were mainly enrichment in connective tissue development. In the PPI network, RB1, CEBPA, PPARG, BATF was the most significantly up-regulated gene in ruptured atherosclerotic samples. The immune cell composition enriched in CD cells and macrophages in the unstable carotid plaque. Conclusions Upregulated RB1, CEBPA, PPARG, BATF and down-regulated SRF, MYOCD, HEY2, GATA6 might perform critical promotional roles in atherosclerotic plaque rupture, furthermore, number and polarization of macrophages may play an important role in vulnerable plaques.

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Genetically targeting the BATF family transcription factors BATF and BATF3 in the mouse abrogates effector T cell activities and enables long-term heart allograft survival

Cited by 10 publications

References 30 publications

Ablation of BATF Alleviates Transplant Rejection via Abrogating the Effector Differentiation and Memory Responses of CD8+ T Cells

Ablation of BATF Alleviates Transplant Rejection via Abrogating the Effector Differentiation and Memory Responses of CD8+ T Cells

The underlying molecular mechanisms and biomarkers of plaque vulnerability based on bioinformatics analysis

The underlying molecular mechanisms and biomarkers of plaque vulnerability based on bioinformatics analysis

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