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在CD4 + T细胞发育的TCR转基因模型中,对特定胸腺内配体的竞争限制了阳性选择。

Competition for specific intrathymic ligands limits positive selection in a TCR transgenic model of CD4+ T cell development.

作者信息

Wong P, Goldrath A W, Rudensky A Y

机构信息

Howard Hughes Medical Institute, Department of Immunology, University of Washington School of Medicine, Seattle 98195, USA.

出版信息

J Immunol. 2000 Jun 15;164(12):6252-9. doi: 10.4049/jimmunol.164.12.6252.

Abstract

Efficient positive selection of a broad repertoire of T cells is dependent on the presentation of a diverse array of endogenous peptides on MHC molecules in the thymus. It is unclear, however, whether the development of individual TCR specificities is influenced by the abundance of their selecting ligands. To examine this, we analyzed positive selection in a transgenic mouse carrying a TCR specific for the human CLIP:I-Ab class II complex. We found that these mice exhibit significantly reduced CD4+ T cell development compared with two other transgenic mice carrying TCRs selected on I-Ab. Moreover, many of the selected cells in these mice express endogenous and transgenic receptors as a consequence of dual TCRalpha expression. Dramatic enhancement of the selection efficiency is observed, however, when fewer transgenic cells populate the thymus in mixed bone marrow chimeras. These results suggest that positive selection is limited by the availability of selecting peptides in the thymus. This becomes apparent when large numbers of thymocytes compete for such peptides in TCR transgenic animals. Under such conditions, thymocytes appear to undergo further TCRalpha gene rearrangement to produce a receptor that may be selected more efficiently by other thymic self-peptides.

摘要

T细胞广泛库的高效阳性选择依赖于胸腺中MHC分子上多种内源性肽的呈递。然而,尚不清楚个体TCR特异性的发育是否受其选择配体丰度的影响。为了对此进行研究,我们分析了携带针对人CLIP:I-Ab II类复合物的TCR的转基因小鼠中的阳性选择。我们发现,与另外两只携带在I-Ab上选择的TCR的转基因小鼠相比,这些小鼠的CD4+ T细胞发育显著减少。此外,由于双重TCRα表达,这些小鼠中许多被选择的细胞同时表达内源性和转基因受体。然而,当混合骨髓嵌合体中胸腺中转基因细胞数量较少时,观察到选择效率显著提高。这些结果表明,阳性选择受胸腺中选择肽可用性的限制。当大量胸腺细胞在TCR转基因动物中竞争此类肽时,这一点变得很明显。在这种情况下,胸腺细胞似乎会经历进一步的TCRα基因重排,以产生一种可能被其他胸腺自身肽更有效地选择的受体。

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