Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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 RORgamma functions in an iNKT cell lineage-specific manner. Further, introgression of a Bcl-x(L) 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.

Original publication

DOI

10.1073/pnas.0408449102

Type

Journal article

Journal

Proc natl acad sci u s a

Publication Date

05/04/2005

Volume

102

Pages

5114 - 5119

Keywords

Animals, Base Sequence, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cell Differentiation, DNA, Complementary, Gene Rearrangement, T-Lymphocyte, Immunity, Innate, Killer Cells, Natural, Lymphopoiesis, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Models, Immunological, Nuclear Receptor Subfamily 1, Group F, Member 3, Radiation Chimera, Receptors, Retinoic Acid, Receptors, Thyroid Hormone, T-Lymphocyte Subsets