CTLA-4 expression by B-1a B cells is essential for immune tolerance
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ABSTRACT:
PROVIDER: PRJNA678235 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13053884_1.fastq.gz | Fastqsanger.gz | |||
| SRR13053884_2.fastq.gz | Fastqsanger.gz | |||
| SRR13053885_1.fastq.gz | Fastqsanger.gz | |||
| SRR13053885_2.fastq.gz | Fastqsanger.gz | |||
| SRR13053886_1.fastq.gz | Fastqsanger.gz |
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Project description:The importance of CTLA-4 regulation of T cell function is well recognized. Studies here report the expression of this immune-regulator in murine B-1a cells, and demonstrate the critical roles CTLA-4 plays in maintaining self-tolerance through regulating these early-developing B cells that express a repertoire enriched for auto-reactivity. By selectively deleting CTLA-4 from B cells, we show that the conditional knockout mice spontaneously generate T follicular helper (Tfh) cells and germinal centers (GC) in spleen; produce autoantibodies; and, later in life, develop autoimmune pathologies. This impaired immune homeostasis results from B-1a dysfunction when they lose CTLA-4. Thus, CTLA-4-deficient B-1a cells up-regulate epigenetic and transcriptional activation programs and show increased self-replenishment. These activated cells further internalize surface IgM, differentiate to antigen-presenting cells and, when reconstituted in normal congenic recipients, induce GC responses and Tfh cells expressing a highly selected repertoire. These findings introduce CTLA-4 regulation of B-1a as a crucial immune-regulatory mechanism.
2020-11-14 | GSE161409 | GEO
Project description:CTLA-4 is an important regulator of T-cell function. Here, we report that expression of this immune-regulator in mouse B-1a cells has a critical function in maintaining self-tolerance by regulating these early-developing B cells that express a repertoire enriched for auto-reactivity. Selective deletion of CTLA-4 from B cells results in mice that spontaneously develop autoantibodies, T follicular helper (Tfh) cells and germinal centers (GCs) in the spleen, and autoimmune pathology later in life. This impaired immune homeostasis results from B-1a cell dysfunction upon loss of CTLA-4. Therefore, CTLA-4-deficient B-1a cells up-regulate epigenetic and transcriptional activation programs and show increased self-replenishment. These activated cells further internalize surface IgM, differentiate into antigen-presenting cells and, when reconstituted in normal IgH-allotype congenic recipient mice, induce GCs and Tfh cells expressing a highly selected repertoire. These findings show that CTLA-4 regulation of B-1a cells is a crucial immune-regulatory mechanism.
| S-EPMC7822855 | biostudies-literature
Project description:The MR is an endocytic receptor, which plays an important role in serum homeostasis and antigen presentation. In this study, we firstly describe an important role of the MR as a direct regulator of CD8+ T cell activity. We could demonstrate that the presence of the MR on DCs impaired the cytotoxicity of activated CD8+ T cells both in vitro and in vivo. This regulatory effect was mediated by a direct interaction of the MR with CD45 on the T cells surface, which abolished CD45 activity. MR-mediated suppression of CD45 resulted in the up-regulation of the inhibitory molecule CTLA-4, which in turn was responsible for the reduced T cell activity. MR-mediated inactivation of CD45, up-regulation of CTLA-4 and T cell inactivation could be circumvented by increased signaling via CD28, which was achieved by DC maturation. These implications point out an important role of the MR in maintaining the balance between tolerance and immunity and might have pivotal implications for the development of vaccination strategies aimed at dampening adaptive immunity. DesTCR T cells were incubated with MR-deficient DCs in the presence of FcMR or isotype controls for the indicated time points. Afterwards, CD8+ T cells were isolated by cell sorting (FACSAria), and immediately lysed in Trizol (Invitrogen) before storage at -80°C for RNA isolation.
2016-08-23 | E-GEOD-45805 | biostudies-arrayexpress
Project description:B-1a cells are important immune cells, serving as the first line of defense against pathogens. B-1a cell undergo a series of alterations during aging and decrease the protection to our body. However, the characteristics of B-1a cells during the aging process are not fully understood. In this study, we discrible transcriptional and epigenetic profiles of B-1a from 3-month-old and 24-month-old mice across both genders. Interestingly，We found that the expression of the transcription factor Bcl11a was positively correlated with the number of B-1a cells in aged male and aged female mice.To further characterize senescent B-1a cells and the mechanisms of Bcl11a regulates B-1a. ATAC-seq and RNA-seq were performed on the B-1a isolated from young male mice (3-month-old),old male mice (24-month-old mice), young female mice (3-month-old),old female mice (24-month-old mice) of C57BL/6,and Bcl11a delated young male mice. CUT&tag was performed on the B-1a isolated from young male mice. Collectively, we provide a comprehensive resource to decode the aging process of B-1a, shedding light on how Bcl11a regulate B-1a cells maintenance.
2025-06-19 | GSE272987 | GEO
Project description:B-1a cells are important immune cells, serving as the first line of defense against pathogens. B-1a cell undergo a series of alterations during aging and decrease the protection to our body. However, the characteristics of B-1a cells during the aging process are not fully understood. In this study, we discrible transcriptional and epigenetic profiles of B-1a from 3-month-old and 24-month-old mice across both genders. Interestingly，We found that the expression of the transcription factor Bcl11a was positively correlated with the number of B-1a cells in aged male and aged female mice.To further characterize senescent B-1a cells and the mechanisms of Bcl11a regulates B-1a. ATAC-seq and RNA-seq were performed on the B-1a isolated from young male mice (3-month-old),old male mice (24-month-old mice), young female mice (3-month-old),old female mice (24-month-old mice) of C57BL/6,and Bcl11a delated young male mice. CUT&tag was performed on the B-1a isolated from young male mice. Collectively, we provide a comprehensive resource to decode the aging process of B-1a, shedding light on how Bcl11a regulate B-1a cells maintenance.
2025-06-19 | GSE272986 | GEO
Project description:B-1a cells are important immune cells, serving as the first line of defense against pathogens. B-1a cell undergo a series of alterations during aging and decrease the protection to our body. However, the characteristics of B-1a cells during the aging process are not fully understood. In this study, we discrible transcriptional and epigenetic profiles of B-1a from 3-month-old and 24-month-old mice across both genders. Interestingly，We found that the expression of the transcription factor Bcl11a was positively correlated with the number of B-1a cells in aged male and aged female mice.To further characterize senescent B-1a cells and the mechanisms of Bcl11a regulates B-1a. ATAC-seq and RNA-seq were performed on the B-1a isolated from young male mice (3-month-old),old male mice (24-month-old mice), young female mice (3-month-old),old female mice (24-month-old mice) of C57BL/6,and Bcl11a delated young male mice. CUT&tag was performed on the B-1a isolated from young male mice. Collectively, we provide a comprehensive resource to decode the aging process of B-1a, shedding light on how Bcl11a regulate B-1a cells maintenance.
2025-06-19 | GSE272985 | GEO
Project description:B-1a cells are important immune cells and are the first line of defence against pathogens. During aging, B-1a cells undergo a series of changes that reduce their protective effects on the body. However, the characteristics of B-1a cells during aging are not fully understood. In this study, we transcriptionally and epigenetically characterised B-1a cells from 3-month-old and 24-month-old mice. Interestingly, we found that the expression of the transcription factor Bcl11a was positively correlated with the number of B-1a cells in old male and old female mice. We performed single-cell sequencing from C57BL/6 young female mice (3 months of age), middle-aged female mice (15 months of age) old female mice (26 months of age) to characterise the senescence transition in female mice.
2025-06-19 | GSE281277 | GEO
Project description:Inflammatory bowel disease (IBD) is a chronic and relapsing immune-mediated disorder characterized by intestinal inflammation and epithelial injury. The underlying causes of IBD are not fully understood, but genetic factors have implicated in genome-wide association studies, including CTLA-4, an essential negative regulator of T cell activation. However, establishing a direct link between CTLA-4 and IBD has been challenging due to the early lethality of CTLA-4 knockout mice. In this study, we identified zebrafish Ctla-4 ortholog and investigated its role in maintaining intestinal immune homeostasis by generating a Ctla-4-deficient (ctla-4-/-) zebrafish line. These mutant zebrafish exhibit reduced weight, along with impaired epithelial barrier integrity and lymphocytic infiltration in their intestines. Transcriptomics analysis revealed upregulation of inflammation-related genes, disturbing immune system homeostasis. Moreover, single-cell RNA-sequencing analysis indicated increased Th2 cells and interleukin 13 expression, along with decreased innate lymphoid cells and upregulated proinflammatory cytokines. Additionally, Ctla-4-deficient zebrafish exhibited reduced diversity and an altered composition of the intestinal microbiota. All these phenotypes closely resemble those found in mammalian IBD. Lastly, supplementation with Ctla-4-Ig successfully alleviated intestinal inflammation in these mutants. Altogether, these findings offer substantial evidence linking CTLA-4 to IBD and establish a new model for investigating pathogenesis and potential treatments.
2024-09-16 | GSE255304 | GEO
Project description:Inflammatory bowel disease (IBD) is a chronic and relapsing immune-mediated disorder characterized by intestinal inflammation and epithelial injury. The underlying causes of IBD are not fully understood, but genetic factors have implicated in genome-wide association studies, including CTLA-4, an essential negative regulator of T cell activation. However, establishing a direct link between CTLA-4 and IBD has been challenging due to the early lethality of CTLA-4 knockout mice. In this study, we identified zebrafish Ctla-4 ortholog and investigated its role in maintaining intestinal immune homeostasis by generating a Ctla-4-deficient (ctla-4-/-) zebrafish line. These mutant zebrafish exhibit reduced weight, along with impaired epithelial barrier integrity and lymphocytic infiltration in their intestines. Transcriptomics analysis revealed upregulation of inflammation-related genes, disturbing immune system homeostasis. Moreover, single-cell RNA-sequencing analysis indicated increased Th2 cells and interleukin 13 expression, along with decreased innate lymphoid cells and upregulated proinflammatory cytokines. Additionally, Ctla-4-deficient zebrafish exhibited reduced diversity and an altered composition of the intestinal microbiota. All these phenotypes closely resemble those found in mammalian IBD. Lastly, supplementation with Ctla-4-Ig successfully alleviated intestinal inflammation in these mutants. Altogether, these findings offer substantial evidence linking CTLA-4 to IBD and establish a new model for investigating pathogenesis and potential treatments.
2024-09-16 | GSE255303 | GEO
Project description:Bcl11a is essential for B-1a cell maintenance during aging
| PRJNA1139750 | ENA