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DAP5/eIF3d 替代 mRNA 翻译机制促进人调节性 T 细胞的分化和免疫抑制。

A DAP5/eIF3d alternate mRNA translation mechanism promotes differentiation and immune suppression by human regulatory T cells.

机构信息

Synthis LLC, 430 East 29th Street, Launch Labs, Alexandria Center for Life Sciences, New York, NY, 10016, USA.

Department of Microbiology, NYU Grossman School of Medicine, New York, NY, 10016, USA.

出版信息

Nat Commun. 2021 Nov 30;12(1):6979. doi: 10.1038/s41467-021-27087-w.

DOI:10.1038/s41467-021-27087-w
PMID:34848685
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8632918/
Abstract

Regulatory T cells (Treg cells) inhibit effector T cells and maintain immune system homeostasis. Treg cell maturation in peripheral sites requires inhibition of protein kinase mTORC1 and TGF-beta-1 (TGF-beta). While Treg cell maturation requires protein synthesis, mTORC1 inhibition downregulates it, leaving unanswered how Treg cells achieve essential mRNA translation for development and immune suppression activity. Using human CD4 T cells differentiated in culture and genome-wide transcription and translation profiling, here we report that TGF-beta transcriptionally reprograms naive T cells to express Treg cell differentiation and immune suppression mRNAs, while mTORC1 inhibition impairs translation of T cell mRNAs but not those induced by TGF-beta. Rather than canonical mTORC1/eIF4E/eIF4G translation, Treg cell mRNAs utilize the eIF4G homolog DAP5 and initiation factor eIF3d in a non-canonical translation mechanism that requires cap-dependent binding by eIF3d directed by Treg cell mRNA 5' noncoding regions. Silencing DAP5 in isolated human naive CD4 T cells impairs their differentiation into Treg cells. Treg cell differentiation is mediated by mTORC1 downregulation and TGF-beta transcriptional reprogramming that establishes a DAP5/eIF3d-selective mechanism of mRNA translation.

摘要

调节性 T 细胞 (Treg 细胞) 抑制效应 T 细胞并维持免疫系统的稳态。外周部位 Treg 细胞的成熟需要抑制蛋白激酶 mTORC1 和 TGF-β-1 (TGF-β)。虽然 Treg 细胞的成熟需要蛋白质合成，但 mTORC1 的抑制会使其下调，这就引出了一个问题，即 Treg 细胞如何实现发育和免疫抑制活性所必需的 mRNA 翻译。本研究使用在培养中分化的人 CD4 T 细胞进行全转录组和翻译组谱分析，报告称 TGF-β 通过转录重编程幼稚 T 细胞表达 Treg 细胞分化和免疫抑制 mRNA，而 mTORC1 的抑制会损害 T 细胞 mRNA 的翻译，但不会损害 TGF-β 诱导的 mRNA 翻译。Treg 细胞 mRNA 利用 eIF4G 同源物 DAP5 和起始因子 eIF3d 进行非典型翻译机制，而不是经典的 mTORC1/eIF4E/eIF4G 翻译，该机制需要 eIF3d 由 Treg 细胞 mRNA 5'非编码区指导的帽依赖性结合。在分离的人幼稚 CD4 T 细胞中沉默 DAP5 会损害其分化为 Treg 细胞。Treg 细胞的分化是由 mTORC1 的下调和 TGF-β 的转录重编程介导的，这建立了一种 DAP5/eIF3d 选择性的 mRNA 翻译机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df39/8632918/02765ac972a0/41467_2021_27087_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df39/8632918/4aac864303db/41467_2021_27087_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df39/8632918/ee9408b4fb66/41467_2021_27087_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df39/8632918/703d7f9ff3cc/41467_2021_27087_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df39/8632918/0039895091ee/41467_2021_27087_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df39/8632918/661777a5776a/41467_2021_27087_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df39/8632918/f1838c9bbab7/41467_2021_27087_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df39/8632918/02765ac972a0/41467_2021_27087_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df39/8632918/4aac864303db/41467_2021_27087_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df39/8632918/b647c12aca37/41467_2021_27087_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df39/8632918/ee9408b4fb66/41467_2021_27087_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df39/8632918/703d7f9ff3cc/41467_2021_27087_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df39/8632918/0039895091ee/41467_2021_27087_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df39/8632918/661777a5776a/41467_2021_27087_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df39/8632918/f1838c9bbab7/41467_2021_27087_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df39/8632918/02765ac972a0/41467_2021_27087_Fig8_HTML.jpg

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