Multiple constraints at the level of TCRa rearrangement impact Vα14i NKT cell development
Multiple constraints at the level of TCRa rearrangement impact Vα14i NKT cell development
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DOI：
10.4049/jimmunol.179.4.2228
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发表时间：
2007-08-15
影响因子：
4.4
通讯作者：
Gapin, Laurent
中科院分区：
文献类型：
--
作者：
Hager, Elizabeth;Hawwari, Abbas;Gapin, Laurent
表达不变V α 14 TCR的CD 1d限制性NKT细胞代表参与多种免疫应答调节的T细胞亚群，包括自身免疫、感染性疾病和癌症。在未成熟胸腺细胞中Va 14与J α 18基因片段的正确重排是产生TCR的先决条件，TCR随后可被胸腺中的CD 1d/自身配体复合物阳性选择并产生NKT细胞群。我们在这里表明，V α 14到J α重排在个体发育过程中的时间调节提供了一个分子的解释，他们的后期出现在胸腺。使用转录因子ROR γ和种系启动子T早期-α和J α 49缺陷的小鼠，我们表明V α和J α使用的发育限制影响NKT细胞发育。最后，我们证明了使用Va 14和Ja 18的重排在没有FynT的情况下正常发生，认为FynT对NKT细胞发育的影响发生在α链重排之后。总之，本研究提供的证据表明，没有定向重排Va 14到Ja 18段，并支持NKT细胞选择的指导性选择模型。
CD1d-restricted NKT cells that express an invariant V alpha 14 TCR represent a subset of T cells implicated in the regulation of several immune responses, including autoimmunity, infectious disease, and cancer. Proper rearrangement of Va14 with the J alpha 18 gene segment in immature thymocytes is a prerequisite to the production of a TCR that can be subsequently positively selected by CD1d/self-ligand complexes in the thymus and gives rise to the NKT cell population. We show here that V alpha 14 to J alpha rearrangements are temporally regulated during ontogeny providing a molecular explanation to their late appearance in the thymus. Using mice deficient for the transcription factor ROR gamma and the germline promoters T early-a and J alpha 49, we show that developmental constraints on both V alpha and J alpha usage impact NKT cell development. Finally, we demonstrate that rearrangements using Va14 and Ja18 occur normally in the absence of FynT, arguing that the effect of FynT on NKT cell development occurs subsequent to a-chain rearrangement. Altogether, this study provides evidence that there is no directed rearrangement of Va14 to Ja18 segments and supports the instructive selection model for NKT cell selection.