期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2005
卷号：102
期号：14
页码：5114-5119
DOI：10.1073/pnas.0408449102
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：T lineage commitment occurs in a discrete, stage-specific manner during thymic ontogeny. Intrathymic precursor transfer experiments and the identification of CD4+8+ double-positive (DP), V{alpha}14J{alpha}18 natural T (iNKT) cells suggest that commitment to this lineage might occur at the DP stage. Nevertheless, this matter remains contentious because others failed to detect V{alpha}14J{alpha}18-positive iNKT cells that are CD4+8+. In resolution to this issue, we demonstrate that retinoic acid receptor-related orphan receptor {gamma} (ROR{gamma})0/0 thymi, which accumulate immature single-positive (ISP) thymocytes that precede the DP stage, do not rearrange V{alpha}14-to-J{alpha}18 gene segments, suggesting that this event occurs at a post-ISP stage. Mixed radiation bone marrow chimeras revealed that ROR{gamma} functions in an iNKT cell lineage-specific manner. Further, introgression of a Bcl-xL transgene into ROR{gamma}0/0 mice, which promotes survival and permits secondary rearrangements of distal V{alpha} and J{alpha} gene segments at the DP stage, rescues V{alpha}14-to-J{alpha}18 recombination. Similarly, introgression of a rearranged V{alpha}14J{alpha}18 transgene into ROR{gamma}0/0 mice results in functional iNKT cells. Thus, our data support the "T cell receptor-instructive (mainstream precursor) model" of iNKT cell lineage specification where V{alpha}14-to-J{alpha}18 rearrangement, positive selection, and iNKT cell lineage commitment occur at or after the DP stage of ontogeny.
