小柯机器人

美国丹娜法伯癌症研究所Ellis L. Reinherz等研究人员合作发现，前T细胞受体自我MHC取样限制胸腺细胞的去分化。这一研究成果于2022年11月21日在线发表在国际学术期刊《自然》上。

研究人员表示，对T淋巴细胞进行编程来区分自我和非自我是一个在胸腺中产生的重要、多步骤过程。通过前T细胞受体（preTCR）的信号传导（这是一个与CD3相关的异质体，包括一个不变的pTα链和一个克隆特异的β链），构成了αβ T细胞系中胸腺细胞发育的一个关键的早期检查点。排列在双阴性（DN）胸腺细胞上的PreTCR与出现在双阳性（DP）胸腺细胞上的αβ TCR一样，通过不同的分子对接策略将肽与胸腺基质上的MHC分子（pMHC）结合起来。

研究人员展示了这些独特的相互作用对胸腺细胞进展的影响。通过使用同步的胎儿胸腺前体培养，在支持基质上存在或不存在pMHC的不同，研究人员确定了在关键胸腺细胞发育过渡时期的单细胞转录组。尽管MHC阴性基质促进了αβ T淋巴细胞的分化，但缺乏pMHC-preTCR的相互作用导致了与去分化相关的胸腺细胞转录程序的偏差。高度增殖的DN和DP亚群出现，具有T细胞淋巴细胞和骨髓性恶性肿瘤的前驱特征。

在B2m/H2-Ab1 MHC基因敲除的小鼠中，各种MHC Ib类蛋白的补偿性上调部分地保护了体内胸腺细胞的进展，尽管随着年龄的增长，传播性DP胸腺肿瘤可能发展。因此，除了为随后的αβ TCR的利用促进β链的拓宽外，preTCR-pMHC的相互作用限制了细胞的可塑性，从而促进正常的胸腺细胞分化和增殖，如果没有，就会导致发育的脆弱性。

附：英文原文

Title: Pre-T cell receptor Self-MHC Sampling Restricts Thymocyte Dedifferentiation

Author: Duke-Cohan, Jonathan S., Akitsu, Aoi, Mallis, Robert J., Messier, Cameron M., Lizotte, Patrick H., Aster, Jon C., Hwang, Wonmuk, Lang, Matthew J., Reinherz, Ellis L.

Issue&Volume: 2022-11-21

Abstract: Programming T lymphocytes to distinguish self from non-self is a vital, multi-step process arising in the thymus1-4. Signalling through the pre-T cell receptor (preTCR), a CD3-associated heterodimer comprising an invariant pTα chain and a clone-specific β chain, constitutes a critical early checkpoint in thymocyte development within the αβ T-cell lineage5,6. PreTCRs arrayed on double negative (DN) thymocytes, like αβ TCRs appearing on double positive (DP) thymocytes, ligate peptides bound to MHC molecules (pMHC) on thymic stroma but via a different molecular docking strategy7-10. Here we show the consequences of those distinctive interactions for thymocyte progression, using synchronized fetal thymic progenitor cultures differing in the presence or absence of pMHC on support stroma, determining single cell transcriptomes at key thymocyte developmental transitions. Although MHC negative stroma fosters αβ T lymphocyte differentiation, the absence of pMHC-preTCR interplay leads to deviant thymocyte transcriptional programming associated with dedifferentiation. Highly proliferative DN and DP subsets with antecedent characteristics of T cell lymphoblastic and myeloid malignancies emerge. Compensatory upregulation of diverse MHC class Ib proteins in B2m/H2-Ab1 MHC knockout mice partially safeguards in vivo thymocyte progression although, with ageing, disseminated DP thymic tumours may develop. Thus, beyond fostering β chain repertoire broadening for subsequent αβ TCR utilization, preTCR-pMHC interaction limits cellular plasticity to facilitate normal thymocyte differentiation and proliferation that, if absent, introduces developmental vulnerabilities.

DOI: 10.1038/s41586-022-05555-7

Source: https://www.nature.com/articles/s41586-022-05555-7

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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