MiR-15/16 clusters restrict effector Treg cell differentiation and function
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA937250 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23568660_1.fastq.gz | Fastqsanger.gz | |||
| SRR23568660_2.fastq.gz | Fastqsanger.gz | |||
| SRR23568661_1.fastq.gz | Fastqsanger.gz | |||
| SRR23568661_2.fastq.gz | Fastqsanger.gz | |||
| SRR23568662_1.fastq.gz | Fastqsanger.gz |
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Project description:Effector regulatory T cells (eTregs) exhibit distinct homeostatic properties and superior suppressor capacities pivotal for controlling immune responses mediated by their conventional T cell counterpart. While the role of microRNAs (miRNAs) in Tregs has been well-established, how miRNAs regulate eTregs remains poorly understood. Here, we demonstrate that miR-15/16 clusters act as key regulators in limiting eTreg responses. Loss of miR-15/16 clusters leads to increased eTreg frequencies with enhanced suppressor function. Consequently, mice with Treg-specific ablation of miR-15/16 clusters display attenuated immune responses during neuroinflammation and upon both infectious and non-infectious challenges. Mechanistically, miR-15/16 clusters exert their regulatory effect in part through repressing IRF4, a transcription factor essential for eTreg differentiation and function. Moreover, miR-15/16 clusters also directly target neuritin, an IRF4-dependent molecule, known for its role in Treg-mediated regulation of plasma cell responses. Together, we identify an miRNA family that controls an important Treg subset and further demonstrate that eTreg responses are tightly regulated at both transcriptional and posttranscriptional levels.
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Project description:Effector regulatory T cells (eTregs) exhibit distinct homeostatic properties and superior suppressor capacities pivotal for controlling immune responses mediated by their conventional T cell counterpart. While the role of microRNAs (miRNAs) in Tregs has been well-established, how miRNAs regulate eTregs remains poorly understood. Here, we demonstrate that miR-15/16 clusters act as key regulators in limiting eTreg responses. Loss of miR-15/16 clusters leads to increased eTreg frequencies with enhanced suppressor function. Consequently, mice with Treg-specific ablation of miR-15/16 clusters display attenuated immune responses during neuroinflammation and upon both infectious and non-infectious challenges. Mechanistically, miR-15/16 clusters exert their regulatory effect in part through repressing IRF4, a transcription factor essential for eTreg differentiation and function. Moreover, miR-15/16 clusters also directly target neuritin, an IRF4-dependent molecule, known for its role in Treg-mediated regulation of plasma cell responses. Together, we identify an miRNA family that controls an important Treg subset and further demonstrate that eTreg responses are tightly regulated at both transcriptional and posttranscriptional levels.
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Project description:The miR-15/16 family is a highly expressed group of tumor suppressor miRNAs that target a large network of genes in T cells to restrict their cell cycle, memory formation and survival. Upon T cell activation, miR-15/16 are downregulated, allowing rapid expansion of differentiated effector T cells to mediate a sustained immune response. Here, using conditional deletion of miR-15/16 in immunosuppressive regulatory T cells (Tregs) that express FOXP3, we identify new functions of the miR-15/16 family in T cell immunity. miR-15/16 are indispensable to maintain peripheral tolerance by securing efficient suppression by a limited number of Tregs. miR-15/16-deficiency alters Treg expression of critical functional proteins including FOXP3, IL2Rα/CD25, CTLA4, PD-1 and IL7Rα/CD127, and results in accumulation of functionally impaired FOXP3loCD25loCD127hi Tregs. Excessive proliferation in the absence of miR-15/16 inhibition of cell cycle programs shifts Treg diversity and produces an effector Treg phenotype characterized by low expression of TCF1, CD25 and CD62L, and high expression of CD44. These Tregs fail to control immune activation of CD4+ effector T cells, leading to spontaneous multi-organ inflammation and increased allergic airway inflammation in a mouse model of asthma. Together, our results demonstrate that miR-15/16 expression in Tregs is essential to maintain immune tolerance.
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Project description:Through their functional diversification, CD4+ T cells play key roles in both driving and constraining immune-mediated pathology. Transcription factors are critical in the generation and maintenance of cellular diversity and negative regulators antagonistic to alternate fates often act in conjunction with positive regulators to stabilize lineage specification1. Polymorphisms within the locus encoding a transcription factor BACH2 are associated with diverse immune-mediated diseases including asthma2, multiple sclerosis3, Crohn¹s disease4-5, coeliac disease6, vitiligo7 and type 1 diabetes8. A role for Bach2 in maintaining immune homeostasis, however, has not been established. Here, we define Bach2 as a broad regulator of immune activation that stabilizes immunoregulatory capacity while repressing the differentiation programmes of multiple effector lineages in CD4+ T cells. Bach2 was required for efficient formation of regulatory (Treg) cells and consequently for suppression of lethal inflammation in a manner that was Treg cell dependent. Assessment of the genome-wide function of Bach2, however, revealed that it represses genes associated with effector cell differentiation. Consequently, its absence during Treg polarization resulted in inappropriate diversion to effector lineages. In addition, Bach2 constrained full effector differentiation within Th1, Th2 and Th17 cell lineages. These findings identify Bach2 as a key regulator of CD4+ T-cell differentiation that prevents inflammatory disease by controlling the balance between tolerance and immunity. The role of Bach2t to regulate immune homeostasis was investigated by mapping DNA binding profiles of Bach2 in iTreg condition. The function of Bach2 was also evaluated by comparing transcriptome in WT and Bach2-deficient iTreg cells and further comparison was done with transcriptome in naive, Th1, Th2, and Th17 conditions.
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