Pre-T cell receptor Self-MHC Sampling Restricts Thymocyte Dedifferentiation,Nature

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Pre-T cell receptor Self-MHC Sampling Restricts Thymocyte Dedifferentiation
Nature ( IF 64.8 ) Pub Date : 2022-11-21 , DOI: 10.1038/s41586-022-05555-7
Jonathan S Duke-Cohan _{1,

2,

3} , Aoi Akitsu _{1,

2,

3} , Robert J Mallis _{1,

2,

4} , Cameron M Messier ₅ , Patrick H Lizotte ₅ , Jon C Aster ₆ , Wonmuk Hwang _{7,

8,

9} , Matthew J Lang _{10,

11} , Ellis L Reinherz _{1,

2,

3}

Affiliation

Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Medicine, Harvard Medical School, Boston, MA, USA.
Department of Dermatology, Harvard Medical School, Boston, MA, USA.
Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Department of Biomedical Engineering, Texas A&M University, College Station, TX, USA.
Department of Materials Science and Engineering, Texas A&M University, College Station, TX, USA.
Department of Physics and Astronomy, Texas A&M University, College Station, TX, USA.
Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA.
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.

Programming T lymphocytes to distinguish self from non-self is a vital, multi-step process arising in the thymus^1-4. 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 lineage^5,6. 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 strategy^7-10. 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.

中文翻译：

前 T 细胞受体自我 MHC 采样限制胸腺细胞去分化

对 T 淋巴细胞进行编程以区分自身与非自身是胸腺中产生的一个至关重要的多步骤过程^1-4。通过前 T 细胞受体 (preTCR) 的信号传递是一种 CD3 相关异二聚体，包含不变的 pTα 链和克隆特异性 β 链，构成 αβ T 细胞谱系内胸腺细胞发育的关键早期检查点^5,6。PreTCR 排列在双阴性 (DN) 胸腺细胞上，就像 αβ TCR 出现在双阳性 (DP) 胸腺细胞上一样，连接肽与胸腺基质上的 MHC 分子 (pMHC) 结合，但通过不同的分子对接策略^7-10。在这里，我们使用支持基质上是否存在 pMHC 的同步胎儿胸腺祖细胞培养物来展示这些独特相互作用对胸腺细胞进展的影响，确定关键胸腺细胞发育转变的单细胞转录组。尽管 MHC 阴性基质促进 αβ T 淋巴细胞分化，但 pMHC-preTCR 相互作用的缺失会导致与去分化相关的异常胸腺细胞转录编程。具有 T 细胞淋巴母细胞和骨髓恶性肿瘤先行特征的高度增殖的 DN 和 DP 亚群出现。B2m / H2-Ab1 MHC 敲除小鼠中多种 MHC Ib 类蛋白的补偿性上调可部分保障体内然而，随着年龄的增长，可能会出现播散性 DP 胸腺肿瘤。因此，除了促进随后 αβ TCR 利用的 β 链库拓宽之外，前 TCR-pMHC 相互作用还限制了细胞可塑性，以促进正常胸腺细胞的分化和增殖，如果不存在，则会引入发育缺陷。

更新日期：2022-11-22

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