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    T cell development is predicated on the successful rearrangement of the TCR gene loci, which encode for Ag-specific receptors. Recombination-activating gene (RAG) 2 is required for TCR gene rearrangements, which occur during specific stages of T cell development. In this study, we differentiated human pluripotent stem cells with a CRISPR/Cas9-directed deletion of the RAG2 gene (RAG2-KO) to elucidate the requirement for the TCR β-chain in mediating β-selection during human T cell development. In stark contrast to mice, human RAG2-KO T lineage progenitors progressed to the CD4+CD8+ double-positive (DP) stage in the absence of TCRβ rearrangements. Nonetheless, RAG2-KO DPs retrovirally transduced to express a rearranged TCR β-chain showed increased survival and proliferation as compared with control-transduced RAG2-KO DPs. Furthermore, transcriptomic analysis showed that TCRβ- and control-transduced RAG2-KO DPs differed in gene pathways related to survival and proliferation. Our results provide important insights as to the distinct requirement for the TCR β-chain during human T cell development. Copyright © 2021 by The American Association of Immunologists, Inc.


    Edward L Y Chen, Patrick M Brauer, Elisa C Martinez, Xiaotian Huang, Ning Yu, Michele K Anderson, Yang Li, Juan Carlos Zúñiga-Pflücker. Cutting Edge: TCR-β Selection Is Required at the CD4+CD8+ Stage of Human T Cell Development. Journal of immunology (Baltimore, Md. : 1950). 2021 May 15;206(10):2271-2276

    PMID: 33941655

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