研究者らが自己免疫疾患と闘う細胞を訓練する鍵となる酵素を特定(UMass Amherst Researchers Identify Enzyme Key to Training Cells to Fight Autoimmune Disorders)

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2024-02-27 マサチューセッツ大学アマースト校

マサチューセッツ大学アマースト校の研究者らが、自己免疫性の希少な障害である再生不良性貧血に焦点を当てた研究を発表した。この研究は、特定の酵素であるPRMT5が、特殊な細胞集団で抑制活性の主要な調節因子であることを明らかにした。再訓練されたiTregsは、マウスモデルでTh1による免疫応答を効果的に減少させ、生存率を著しく向上させることが示された。

<関連情報>

PRMT5がIL-12治療に対するTh1様iTregsのエピジェネティック変化を制御することを発見
PRMT5 regulates epigenetic changes in suppressive Th1-like iTregs in response to IL-12 treatment

Nidhi Jadon,Sudarvili Shanthalingam,Gregory N. Tew,Lisa M. Minter
Frontiers in Immunology  Published:08 January 2024
DOI:https://doi.org/10.3389/fimmu.2023.1292049

研究者らが自己免疫疾患と闘う細胞を訓練する鍵となる酵素を特定(UMass Amherst Researchers Identify Enzyme Key to Training Cells to Fight Autoimmune Disorders)

Background: Induced regulatory T cells (iTregs) are a heterogeneous population of immunosuppressive T cells with therapeutic potential. Treg cells show a range of plasticity and can acquire T effector-like capacities, as is the case for T helper 1 (Th1)-like iTregs. Thus, it is important to distinguish between functional plasticity and lineage instability. Aplastic anemia (AA) is an autoimmune disorder characterized by immune-mediated destruction of hematopoietic stem and progenitor cells in the bone marrow (BM). Th1-like 1 iTregs can be potent suppressors of aberrant Th1-mediated immune responses such as those that drive AA disease progression. Here we investigated the function of the epigenetic enzyme, protein arginine methyltransferase 5 (PRMT5), its regulation of the iTreg-destabilizing deacetylase, sirtuin 1 (Sirt1) in suppressive Th1-like iTregs, and the potential for administering Th1-like iTregs as a cell-based therapy for AA.

Methods: We generated Th1-like iTregs by culturing iTregs with IL-12, then assessed their suppressive capacity, expression of iTreg suppression markers, and enzymatic activity of PRMT5 using histone symmetric arginine di-methylation (H3R2me2s) as a read out. We used ChIP sequencing on Th1 cells, iTregs, and Th1-like iTregs to identify H3R2me2s-bound genes unique to Th1-like iTregs, then validated targets using CHiP-qPCR. We knocked down PRMT5 to validate its contribution to Th1-like iTreg lineage commitment. Finally we tested the therapeutic potential of Th1-like iTregs using a Th1-mediated mouse model of AA.

Results: Exposing iTregs to the Th1 cytokine, interleukin-12 (IL-12), during early events of differentiation conveyed increased suppressive function. We observed increased PRMT5 enzymatic activity, as measured by H3R2me2s, in Th1-like iTregs, which was downregulated in iTregs. Using ChIP-sequencing we discovered that H3R2me2s is abundantly bound to the Sirt1 promoter region in Th1-like iTregs to negatively regulate its expression. Furthermore, administering Th1-like iTregs to AA mice provided a survival benefit.

Conclusions: Knocking down PRMT5 in Th1-like iTregs concomitantly reduced their suppressive capacity, supporting the notion that PRMT5 is important for the superior suppressive capacity and stability of Th1-like iTregs. Conclusively, therapeutic administration of Th1-like iTregs in a mouse model of AA significantly extended their survival and they may have therapeutic potential.

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