title: Commitment toward the natural T (iNKT) cell lineage occurs at the CD4+8+ stage of thymic ontogeny.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Jelena S
authors.initials: JS
authors.lastname: Bezbradica
authors.forename: Timothy
authors.initials: T
authors.lastname: Hill
authors.forename: Aleksandar K
authors.initials: AK
authors.lastname: Stanic
authors.forename: Luc
authors.initials: L
authors.lastname: Van Kaer
authors.forename: Sebastian
authors.initials: S
authors.lastname: Joyce
mesh_terms: D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation; D018076:DNA, Complementary / Q000235:genetics; D015329:Gene Rearrangement, T-Lymphocyte; D007113:Immunity, Innate; D007694:Killer Cells, Natural / Q000166:cytology* / Q000276:immunology*; D038041:Lymphopoiesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018448:Models, Immunological; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D011828:Radiation Chimera / Q000235:genetics / Q000276:immunology; D018168:Receptors, Retinoic Acid / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D011988:Receptors, Thyroid Hormone / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology*
chemical_list: D018076:DNA, Complementary; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; C539901:Rorc protein, mouse